IL-1/IL-1R Signaling in Head and Neck Cancer

Sven E Niklander, Craig Murdoch, Keith D Hunter, Sven E Niklander, Craig Murdoch, Keith D Hunter

Abstract

Decades ago, the study of cancer biology was mainly focused on the tumor itself, paying little attention to the tumor microenvironment (TME). Currently, it is well recognized that the TME plays a vital role in cancer development and progression, with emerging treatment strategies focusing on different components of the TME, including tumoral cells, blood vessels, fibroblasts, senescent cells, inflammatory cells, inflammatory factors, among others. There is a well-accepted relationship between chronic inflammation and cancer development. Interleukin-1 (IL-1), a potent pro-inflammatory cytokine commonly found at tumor sites, is considered one of the most important inflammatory factors in cancer, and has been related with carcinogenesis, tumor growth and metastasis. Increasing evidence has linked development of head and neck squamous cell carcinoma (HNSCC) with chronic inflammation, and particularly, with IL-1 signaling. This review focuses on the most important members of the IL-1 family, with emphasis on how their aberrant expression can promote HNSCC development and metastasis, highlighting possible clinical applications.

Keywords: Anakinra (PubChem CID: 90470007); IL-1; head and neck cancer; oral cancer; squamous cell carcinoma; tumor microenvironment.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Niklander, Murdoch and Hunter.

Figures

Figure 1
Figure 1
(A) IL-1α and (B) IL-1β forms. (C) IL-1R1 agonist receptor. To be active, IL-1R1 needs the binding of IL-1RAcP. Both IL-1R1 and IL-1RAcP have a TIR domain, which after a series of phosphorylation following IL-1 binding, activate NF-kB. (D) IL-1R2 decoy receptor binds to IL-1 without triggering any agonist action as lacks of a TIR domain. (E) IL-1RA variants bind to IL-1R1, blocking the binding of IL-1 without recruiting IL-1RAcP, thus triggers no agonist action. This image was created with Biorender.
Figure 2
Figure 2
Comparison of IL-1α expression and regulation in normal head and neck keratinocytes (A) and in cancerous head and neck keratinocytes (B). (A) Normal keratinocytes express low levels of IL-1α, which is not normally secreted, and is regulated by icIL1RA, which is expressed in abundancy to efficiently counteract IL-1α actions. This balance secure low NF-kB activity with low production of other inflammatory molecules, such as IL-6 and CXCL-8. (B) In cancerous head and neck keratinocytes, icIL-1RA expression is downregulated, whereas IL-1R1 and IL-1α are constitutively upregulated, generating an imbalance in IL-1 regulation. IL-1α can localize intracellularly and interact directly to the nucleus, can be attached to the cellular membrane (membrane IL-1α) or can be released to the extracellular space. Membrane and secreted IL-1α can both bind to IL-1R1 receptors and activate NF- κB and AP-1 transduction pathways, resulting in the release of IL-6 and CXCL8, which are considered oncogenic cytokines as are associated with tumor growth and metastasis. Also, intranuclear IL-1α can interact directly with the nucleus inducing NF-κB activation in a non-IL-1R1 dependent manner. This also results in the release of IL-6 and CXCL8, which are both overexpressed in HNSCC. This image was created with Biorender.
Figure 3
Figure 3
Different examples of how IL-1βcan promote cancer progression. IL-1β can be produced by tumor cells (A) or by other cells of the TME (B). (i) IL-1β produced by tumor cells stimulates CXCL8 release from normal oral fibroblasts, which increases tumor growth. (ii) IL-1β stimulates CXCL1 and CXCL8 production by CAFs and tumor cells which attracts neutrophils to the TME, and neutrophil accumulation has been related with poor outcome in HNSCC. (iii) IL-1β released by tumor cells induces CXCL-1 and MMP-1 secretion by CAFs. This induces invasion and migration of cancer cells. Also, secreted IL-1β can act in a paracrine way inducing fascine release, which helps in the degradation of the extracellular matrix and invasion. (iv) TAMs produce IL-1β to stimulate cancerous cells to produce VEGF and CXCL8, inducing angiogenesis. (v) IL-1β produced by CAFs induces the release of CCL22 by tumor cells, which recruits T regulatory cells, who have been associated with worse prognosis. This image was created with Biorender.

References

    1. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. (2000) 248:171–83. 10.1046/j.1365-2796.2000.00742.x
    1. Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y, et al. . The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev. (2006) 25:387–408. 10.1007/s10555-006-9004-4
    1. Niklander SE. Inflammatory mediators in oral cancer: pathogenic mechanisms and diagnostic potential. Front Oral Health. (2021) 2. 10.3389/froh.2021.642238
    1. Portier M, Zhang XG, Ursule E, Lees D, Jourdan M, Bataille R, et al. . Cytokine gene expression in human multiple myeloma. Br J Haematol. (1993) 85:514–20. 10.1111/j.1365-2141.1993.tb03341.x
    1. Voronov E, Dinarello CA, Apte RN. Interleukin-1alpha as an intracellular alarmin in cancer biology. Semin Immunol. (2018) 38:3–14. 10.1016/j.smim.2018.10.006
    1. Mantovani A, Barajon I, Garlanda C. IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol Rev. (2018) 281:57–61. 10.1111/imr.12614
    1. Elaraj DM, Weinreich DM, Varghese S, Puhlmann M, Hewitt SM, Carroll NM, et al. . The role of interleukin 1 in growth and metastasis of human cancer xenografts. Clin Cancer Res. (2006) 12:1088–96. 10.1158/1078-0432.CCR-05-1603
    1. Rao SK, Pavicevic Z, Du Z, Kim JG, Fan M, Jiao Y, et al. . Pro-inflammatory genes as biomarkers and therapeutic targets in oral squamous cell carcinoma. J Biol Chem. (2010) 285:32512–21. 10.1074/jbc.M110.150490
    1. Goertzen C, Mahdi H, Laliberte C, Meirson T, Eymael D, Gil-Henn H, et al. . Oral inflammation promotes oral squamous cell carcinoma invasion. Oncotarget. (2018) 9:29047–63. 10.18632/oncotarget.25540
    1. Al-Sahaf S, Hendawi NB, Ollington B, Bolt R, Ottewell PD, Hunter KD, et al. . Increased abundance of tumour-associated neutrophils in hpv-negative compared to HPV-positive oropharyngeal squamous cell carcinoma is mediated by IL-1R Signalling. Front Oral Health. (2021) 2. 10.3389/froh.2021.604565
    1. Al-Sahaf S, Hunter KD, Bolt R, Ottewell PD, Murdoch C. The IL-1/IL-1R axis induces greater fibroblast-derived chemokine release in human papillomavirus-negative compared to positive oropharyngeal cancer. Int J Cancer. (2019) 144:334–44. 10.1002/ijc.31852
    1. Alves AM, Diel LF, Lamers ML. Macrophages and prognosis of oral squamous cell carcinoma: A systematic review. J Oral Pathol Med. (2018) 47:460–7. 10.1111/jop.12643
    1. Trellakis S, Bruderek K, Dumitru CA, Gholaman H, Gu X, Bankfalvi A, et al. . Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int J Cancer. (2011) 129:2183–93. 10.1002/ijc.25892
    1. Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, et al. . Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer. (2014) 110:489–500. 10.1038/bjc.2013.639
    1. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. (2013) 39:1003–18. 10.1016/j.immuni.2013.11.010
    1. Dinarello CA. Introduction to the interleukin-1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity. Immunol Rev. (2018) 281:5–7. 10.1111/imr.12624
    1. Mantovani A, Dinarello CA, Molgora M, Garlanda C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity. (2019) 50:778–95. 10.1016/j.immuni.2019.03.012
    1. Palomo J, Dietrich D, Martin P, Palmer G, Gabay C. The interleukin (IL)-1 cytokine family–Balance between agonists and antagonists in inflammatory diseases. Cytokine. (2015) 76:25–37. 10.1016/j.cyto.2015.06.017
    1. Dower SK, Urdal DL. The interleukin-1 receptor. Immunol Today. (1987) 8:46–51. 10.1016/0167-5699(87)90238-6
    1. Zheng Y, Humphry M, Maguire JJ, Bennett MR, Clarke MC. Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1alpha, controlling necrosis-induced sterile inflammation. Immunity. (2013) 38:285–95. 10.1016/j.immuni.2013.01.008
    1. Kobayashi Y, Yamamoto K, Saido T, Kawasaki H, Oppenheim JJ, Matsushima K. Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1 alpha. Proc Natl Acad Sci U S A. (1990) 87:5548–52. 10.1073/pnas.87.14.5548
    1. Gayle RB, Poindexter K, Cosman D, Dower SK, Gillis S, Hopp T, et al. . Identification of regions in interleukin-1 alpha important for activity. J Biological Chemistry. (1993) 268:22105–11. 10.1016/S0021-9258(20)80654-1
    1. Labriola-Tompkins E, Chandran C, Varnell TA, Madison VS, Ju G. Structure-function analysis of human IL-1 alpha: identification of residues required for binding to the human type I IL-1 receptor. Protein Eng. (1993) 6:535–9. 10.1093/protein/6.5.535
    1. Kim B, Lee Y, Kim E, Kwak A, Ryoo S, Bae SH, et al. . The Interleukin-1alpha Precursor is biologically active and is likely a key alarmin in the IL-1 family of cytokines. Front Immunol. (2013) 4:391. 10.3389/fimmu.2013.00391
    1. Dinarello CA. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Intern Rev Immunol. (1998) 16:457–99. 10.3109/08830189809043005
    1. Dinarello CA, Thompson RC. Blocking IL-I: interleukin I receptor antagonistin vivo andin vitro. Immunol Today. (1991) 12:404–10. 10.1016/0167-5699(91)90142-G
    1. Hammerberg C, Arend WP, Fisher GJ, Chan LS, Berger AE, Haskill JS, et al. . Interleukin-1 receptor antagonist in normal and psoriatic epidermis. J Clin Invest. (1992) 90:571–83. 10.1172/JCI115896
    1. Maier JA, Statuto M, Ragnotti G. Endogenous interleukin 1 alpha must be transported to the nucleus to exert its activity in human endothelial cells. Mol Cell Biol. (1994) 14:1845–51. 10.1128/mcb.14.3.1845-1851.1994
    1. Di Paolo NC, Shayakhmetov DM. Interleukin 1alpha and the inflammatory process. Nat Immunol. (2016) 17:906–13. 10.1038/ni.3503
    1. Maier JA, Voulalas P, Roeder D, Maciag T. Extension of the life-span of human endothelial cells by an interleukin-1 alpha antisense oligomer. Science (New York, NY: ). (1990) 249:1570–4. 10.1126/science.2218499
    1. Mariotti M, Castiglioni S, Bernardini D, Maier JA. Interleukin 1 alpha is a marker of endothelial cellular senescent. Immunity & ageing: I & A. (2006) 3:4. 10.1186/1742-4933-3-4
    1. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, et al. . A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. (2013) 15:978–90. 10.1038/ncb2784
    1. Corradi A, Franzi AT, Rubartelli A. Synthesis and secretion of interleukin-1 alpha and interleukin-1 receptor antagonist during differentiation of cultured keratinocytes. Exp Cell Res. (1995) 217:355–62. 10.1006/excr.1995.1097
    1. Cohen I, Rider P, Vornov E, Tomas M, Tudor C, Wegner M, et al. . IL-1alpha is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep. (2015) 5:14756. 10.1038/srep14756
    1. Kawaguchi Y, Hara M, Wright TM. Endogenous IL-1alpha from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. J Clin Invest. (1999) 103:1253–60. 10.1172/JCI4304
    1. Wolf JS, Chen Z, Dong G, Sunwoo JB, Bancroft CC, Capo DE, et al. . IL (Interleukin)-1 promotes nuclear factor- B and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. Clinical Cancer Research. (2001) 7:1812–20.
    1. Orjaloa AV, Bhaumika D, Genglera BK, Scotta GK, Campisi J. Cell surface-bound IL-1 is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. PNAS. (2009) 106:17031–6. 10.1073/pnas.0905299106
    1. Werman A, Werman-Venkert R, White R, Lee JK, Werman B, Krelin Y, et al. . The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription. Proc Natl Acad Sci U S A. (2004) 101:2434–9. 10.1073/pnas.0308705101
    1. Wessendorf JH, Garfinkel S, Zhan X, Brown S, Maciag T. Identification of a nuclear localization sequence within the structure of the human interleukin-1 alpha precursor. J Biol Chem. (1993) 268:22100–4. 10.1016/S0021-9258(20)80653-X
    1. Stevenson FT, Turck J, Locksley RM, Lovett DH. The N-terminal propiece of interleukin 1 is a transforming nuclear oncoprotein. Cell Biology. (1997) 94:508–13. 10.1073/pnas.94.2.508
    1. Buryskova M, Pospisek M, Grothey A, Simmet T, Burysek L. Intracellular interleukin-1alpha functionally interacts with histone acetyltransferase complexes. J Biol Chem. (2004) 279:4017–26. 10.1074/jbc.M306342200
    1. McMahon GA, Garfinkel S, Prudovsky I, Hu X, Maciag T. Intracellular precursor interleukin (IL)-1α, but not mature IL-1α, is able to regulate human endothelial cell migration in vitro. J Biol Chem. (1997) 272:28202–5. 10.1074/jbc.272.45.28202
    1. Palmer G, Trolliet S, Talabot-Ayer D, Mezin F, Magne D, Gabay C. Pre-interleukin-1alpha expression reduces cell growth and increases interleukin-6 production in SaOS-2 osteosarcoma cells: Differential inhibitory effect of interleukin-1 receptor antagonist (icIL-1Ra1). Cytokine. (2005) 31:153–60. 10.1016/j.cyto.2005.03.007
    1. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. (1996) 87:2095–147. 10.1182/blood.V87.6.2095.bloodjournal8762095
    1. Rider P, Carmi Y, Guttman O, Braiman A, Cohen I, Voronov E, et al. . IL-1alpha and IL-1beta recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol. (2011) 187:4835–43. 10.4049/jimmunol.1102048
    1. Kostura MJ, Tocci MJ, Limjuco G, Chin J, Cameron P, Hillman AG, et al. . Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci U S A. (1989) 86:5227–31. 10.1073/pnas.86.14.5227
    1. Joosten LA, Netea MG, Dinarello CA. Interleukin-1beta in innate inflammation, autophagy and immunity. Semin Immunol. (2013) 25:416–24. 10.1016/j.smim.2013.10.018
    1. Dinarello CA, Ikejima T, Warner SJ, Orencole SF, Lonnemann G, Cannon JG, et al. . Interleukin 1 induces interleukin 1. I Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. (1987) 139:1902–10.
    1. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. (2009) 27:519–50. 10.1146/annurev.immunol.021908.132612
    1. Jobling SA, Auron PE, Gurka G, Webb AC, McDonald B, Rosenwasser LJ, et al. . Biological activity and receptor binding of human prointerleukin-1 beta and subpeptides. J Biol Chem. (1988) 263:16372–8. 10.1016/S0021-9258(18)37603-8
    1. Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood. (1991) 77:1627–52. 10.1182/blood.V77.8.1627.bloodjournal7781627
    1. Luheshi NM, Rothwell NJ, Brough D. Dual functionality of interleukin-1 family cytokines: implications for anti-interleukin-1 therapy. Br J Pharmacol. (2009) 157:1318–29. 10.1111/j.1476-5381.2009.00331.x
    1. Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, et al. . IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A. (2003) 100:2645–50. 10.1073/pnas.0437939100
    1. Niklander S, Bordagaray MJ, Fernández A, Hernández M. Vascular endothelial growth factor: a translational view in oral non-communicable diseases. Biomolecules. (2021) 11:85. 10.3390/biom11010085
    1. Rigante D, Frediani B, Cantarini L. A Comprehensive overview of the hereditary periodic fever syndromes. Clinical Rev Allergy Immunol. (2016) 54:446–53. 10.1007/s12016-016-8537-8
    1. Cohen J. The immunopathogenesis of sepsis. Nature. (2002) 420:885–91. 10.1038/nature01326
    1. Giacomelli R, Ruscitti P, Alvaro S, Ciccia F, Liakouli V, Di Benedetto P, et al. . IL-1beta at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone? Expert Rev Clin Immunol. (2016) 1–7. 10.1586/1744666X.2016.1168293
    1. Kim RY, Pinkerton JW, Gibson PG, Cooper MA, Horvat JC, Hansbro PM. Inflammasomes in COPD and neutrophilic asthma. Thorax. (2015) 70:1199–201. 10.1136/thoraxjnl-2014-206736
    1. Mosley B, Urdal DL, Prickett KS, Larsen A, Cosman D, Conlon PJ, et al. . The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. J Biol Chem. (1987) 262:2941–4. 10.1016/S0021-9258(18)61450-4
    1. Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA, Ju G. Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem. (1995) 270:13757–65. 10.1074/jbc.270.23.13757
    1. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. (2018) 281:8–27. 10.1111/imr.12621
    1. Cullinan EB, Kwee L, Nunes P, Shuster DJ, Ju G, McIntyre KW, et al. . IL-1 receptor accessory protein is an essential component of the IL-1 receptor. J Immunol. (1998) 161:5614–20.
    1. Gallis B, Prickett KS, Jackson J, Slack J, Schooley K, Sims JE, et al. . IL-1 induces rapid phosphorylation of the IL-1 receptor. J Immunol. (1989) 143:3235–40.
    1. Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal. (2010) 3:cm1. 10.1126/scisignal.3105cm1
    1. Niklander SE, Crane HL, Darda L, Lambert DW, Hunter KD. The role of icIL-1RA in keratinocyte senescence and development of the senescence-associated secretory phenotype. J Cell Sci. (2021) 134. 10.1242/jcs.252080
    1. Sun Y, Zhu D, Wang G, Wang D, Zhou H, Liu X, et al. . Pro-inflammatory cytokine IL-1β up-regulates CXC chemokine receptor 4 via Notch and ERK signaling pathways in tongue squamous cell carcinoma. PLoS ONE. (2015) 10:e0132677. 10.1371/journal.pone.0132677
    1. Colotta F, Dower SK, Sims JE, Mantovani A. The type II 'decoy' receptor: a novel regulatory pathway for interleukin 1. Immunol Today. (1994) 15:562–6. 10.1016/0167-5699(94)90217-8
    1. Colotta F, Re F, Muzio M, Bertini R, Polentarutti N, Sironi M, et al. . Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science (New York, NY: ).(1993) 261:472–5. 10.1126/science.8332913
    1. Kuhn PH, Marjaux E, Imhof A, De Strooper B, Haass C, Lichtenthaler SF. Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase. J Biol Chem. (2007) 282:11982–95. 10.1074/jbc.M700356200
    1. Arend WP, Joslin FG, Thompson RC, Hannum CH. An IL-1 inhibitor from human monocytes. Production and characterization of biologic properties. J Immunol. (1989) 143:1851–8.
    1. Kurzrock R, Hickish T, Wyrwicz L, Saunders M, Wu Q, Stecher M, et al. . Interleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-class true human interleukin-1alpha antibody, in a phase III randomized study of advanced colorectal cancer. Oncoimmunology. (2019) 8:1551651. 10.1080/2162402X.2018.1551651
    1. Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, et al. . Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. (1990) 343:336–43. 10.1038/343336a0
    1. Arend WP, Welgus HG, Thompson RC, Eisenberg SP. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. (1990) 85:1694–7. 10.1172/JCI114622
    1. Arend WP, Joslin FG, Massoni RJ. Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor. J Immunol. (1985) 134:3868–75.
    1. Haskill S, Martin G, Van Le L, Morris J, Peace A, Bigler CF, et al. . cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Cell Biology. (1991) 88:3681–5. 10.1073/pnas.88.9.3681
    1. Muzio M, Polentarutti N, Sironi M, Poli G, De Gioia L, Introna M, et al. . Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist. J Exp Med. (1995) 182:623–8. 10.1084/jem.182.2.623
    1. Malyak M, Guthridge JM, Hance KR, Dower SK, Freed JH, Arend WP. Characterization of a low molecular weight isoform of IL-1 receptor antagonist. J Immunol. (1998) 161:1997–2003.
    1. Malyak M, Smith MF, Abel AA, Hance KR, Arend WP. The differential production of three forms of IL-1 receptor antagonist by human neutrophils and monocytes. J Immunol. (1998) 161:2004–10.
    1. La E, Rundhaug JE, Fischer SM. Role of intracellular interleukin-1 receptor antagonist in skin carcinogenesis. Mol Carcinog. (2001) 30:218–23. 10.1002/mc.1031
    1. Shiiba M, Saito K, Yamagami H, Nakashima D, Higo M, Kasamatsu A, et al. . Interleukin-1 receptor antagonist (IL1RN) is associated with suppression of early carcinogenic events in human oral malignancies. Int J Oncol. (2015) 46:1978–84. 10.3892/ijo.2015.2917
    1. Lee JK, Kim SH, Lewis EC, Azam T, Reznikov LL, Dinarello CA. Differences in signaling pathways by IL-1beta and IL-18. Proc Natl Acad Sci U S A. (2004) 101:8815–20. 10.1073/pnas.0402800101
    1. Naik SM, Cannon G, Burbach GJ, Singh SR, Swerlick RA, Wilcox JN, et al. . Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J Invest Dermatol. (1999) 113:766–72. 10.1046/j.1523-1747.1999.00750.x
    1. Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, et al. . IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci U S A. (2007) 104:282–7. 10.1073/pnas.0606854104
    1. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. . Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. (2011) 89:432–7. 10.1016/j.ajhg.2011.07.022
    1. Mora J, Schlemmer A, Wittig I, Richter F, Putyrski M, Frank AC, et al. . Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses. J Mol Cell Biol. (2016) 8:426–38. 10.1093/jmcb/mjw006
    1. Boutet MA, Najm A, Bart G, Brion R, Touchais S, Trichet V, et al. . IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro. Ann Rheum Dis. (2017) 76:1304–12. 10.1136/annrheumdis-2016-210630
    1. Perrier S, Kherratia B, Deschaumes C, Ughetto S, Kemeny L. IL-1ra and IL-1 production in human oral mucosal epithelial cells in culture: differential modulation by TGF-~1 and IL-4. Clin Exp Immunol. (2002) 127:53–9. 10.1046/j.1365-2249.2002.01685.x
    1. Mizutani H, Black R, Kupper TS. Human keratinocytes produce but do not process pro-interleukin-1 (IL-1) beta. Different strategies of IL-1 production and processing in monocytes and keratinocytes. J Clin Invest. (1991) 87:1066–71. 10.1172/JCI115067
    1. Garat C, Arend WP. Intracellular IL-1Ra type 1 inhibits IL-1-induced IL-6 and IL-8 production in Caco-2 intestinal epithelial cells through inhibition of p38 mitogen-activated protein kinase and NF-kappaB pathways. Cytokine. (2003) 23:31–40. 10.1016/S1043-4666(03)00182-0
    1. Phillips WG, Feldmann M, Breathnach SM, Brennan FM. Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-la and IL-1 receptor antagonist. Clin Exp Immunol. (1995) 101:177–82. 10.1111/j.1365-2249.1995.tb02295.x
    1. Banda NK, Guthridge C, Sheppard D, Cairns KS, Muggli M, Bech-Otschir D, et al. . Intracellular IL-1 receptor antagonist type 1 inhibits IL-1-induced cytokine production in keratinocytes through binding to the third component of the COP9 signalosome. J Immunol. (2005) 174:3608–16. 10.4049/jimmunol.174.6.3608
    1. Groves RW, Giri J, Sims J, Dower SK, Kupper TS. Inducible expression of type 2 IL-1 receptors by cultured human keratinocytes. Implications for IL-1-mediated processes in epidermis. J Immunol. (1995) 154:4065–72.
    1. Kondo M, Yamato M, Takagi R, Namiki H, Okano T. The regulation of epithelial cell proliferation and growth by IL-1 receptor antagonist. Biomaterials. (2013) 34:121–9. 10.1016/j.biomaterials.2012.09.036
    1. Dubost JJ, Perrier S, Afane M, Viallard JL, Roux-Lombard P, Baudet-Pommel M, et al. . IL-1 receptor antagonist in saliva; characterization in normal saliva and reduced concentration in Sjogren's syndrome (SS). Clin Exp Immunol. (1996) 106:237–42. 10.1046/j.1365-2249.1996.d01-824.x
    1. Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer. (2015) 15:397–408. 10.1038/nrc3960
    1. Davalos AR, Coppe JP, Campisi J, Desprez PY. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev. (2010) 29:273–83. 10.1007/s10555-010-9220-9
    1. Woods RV, Adler-Storthz K, Dayman GL, Francis GM, Grimm EA. Interleukin-1 regulates interleukin-6 secretion in human oral squamous cell carcinoma in vitro: possible influence of p53 but not human papillomavirus E6/E. Cancer Res. (1998) 58:3142–9.
    1. Lee CH, Chang JS, Syu SH, Wong TS, Chan JY, Tang YC, et al. . IL-1beta promotes malignant transformation and tumor aggressiveness in oral cancer. J Cell Physiol. (2015) 230:875–84. 10.1002/jcp.24816
    1. von Biberstein SE, Spiro JD, Lindquist R, Kreutzer DL. Interleukin-1 receptor antagonist in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. (1996) 122:751–9. 10.1001/archotol.1996.01890190047012
    1. Leon X, Bothe C, Garcia J, Parreno M, Alcolea S, Quer M, et al. . Expression of IL-1alpha correlates with distant metastasis in patients with head and neck squamous cell carcinoma. Oncotarget. (2015) 6:37398–409. 10.18632/oncotarget.6054
    1. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. . Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. (2008) 6:2853–68. 10.1371/journal.pbio.0060301
    1. Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell. (2004) 6:447–58. 10.1016/j.ccr.2004.09.028
    1. Ancrile B, Lim KH, Counter CM. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. (2007) 21:1714–9. 10.1101/gad.1549407
    1. Loaiza N, Demaria M. Cellular senescence and tumor promotion: Is aging the key? Biochim Biophys Acta. (2016) 1865:155–67. 10.1016/j.bbcan.2016.01.007
    1. Yang X, Cheng H, Chen J, Wang R, Saleh A, Si H, et al. . Head and neck cancers promote an inflammatory transcriptome through coactivation of classic and alternative NF-κB pathways. Cancer Immunol Res. (2019) 7:1760–74. 10.1158/2326-6066.CIR-18-0832
    1. Zhang J, Peng B. NF-kappaB promotes iNOS and VEGF expression in salivary gland adenoid cystic carcinoma cells and enhances endothelial cell motility in vitro. Cell Prolif. (2009) 42:150–61. 10.1111/j.1365-2184.2009.00588.x
    1. Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, et al. . Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. (2007) 26:7445–56. 10.1038/sj.onc.1210546
    1. Nakayama H, Ikebe T, Beppu M, Shirasuna K. High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer. (2001) 92:3037–44. 10.1002/1097-0142(20011215)92:12<3037::AID-CNCR10171>;2-#
    1. Jimi E, Kokabu S, Matsubara T, Nakatomi C, Matsuo K, Watanabe S. NF-κB acts as a multifunctional modulator in bone invasion by oral squamous cell carcinoma. Oral Science International. (2016) 13:1–6. 10.1016/S1348-8643(15)00038-5
    1. Tanaka T, Nakayama H, Yoshitake Y, Irie A, Nagata M, Kawahara K, et al. . Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma. Cancer Sci. (2012) 103:455–63. 10.1111/j.1349-7006.2011.02174.x
    1. Duffey DC, Chen Z, Dong G, Ondrey FG, Wolf JS, Brown K, et al. . Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor-kappaB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res. (1999) 59:3468–74.
    1. Wu D, Wu P, Zhao L, Huang L, Zhang Z, Zhao S, et al. . NF-κB Expression and outcomes in solid tumors: A systematic review and meta-analysis. Medicine (Baltimore: ). (2015) 94:e1687. 10.1097/MD.0000000000001687
    1. Alam M, Kashyap T, Pramanik KK, Singh AK, Nagini S, Mishra R. The elevated activation of NFκB and AP-1 is correlated with differential regulation of Bcl-2 and associated with oral squamous cell carcinoma progression and resistance. Clin Oral Investig. (2017) 21:2721–31. 10.1007/s00784-017-2074-6
    1. Lakhanpal M, Yadav DS, Devi TR, Singh LC, Singh KJ, Latha SP, et al. . Association of interleukin-1beta−511 C/T polymorphism with tobacco-associated cancer in northeast India: a study on oral and gastric cancer. Cancer Genet. (2014) 207:1–11. 10.1016/j.cancergen.2014.01.002
    1. Wu T, Hong Y, Jia L, Wu J, Xia J, Wang J, et al. . Modulation of IL-1beta reprogrammes the tumor microenvironment to interrupt oral carcinogenesis. Sci Rep. (2016) 6:20208. 10.1038/srep20208
    1. Hazuda DJ, Strickler J, Kueppers F, Simon PL, Young PR. Processing of precursor interleukin 1 beta and inflammatory disease. J Biol Chem. (1990) 265:6318–22. 10.1016/S0021-9258(19)39328-7
    1. He KF, Zhang L, Huang CF, Ma SR, Wang YF, Wang WM, et al. . CD163+ tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma. Biomed Res Int. (2014) 2014:838632. 10.1155/2014/838632
    1. Bae JY, Kim EK, Yang DH, Zhang X, Park YJ, Lee DY, et al. . Reciprocal interaction between carcinoma-associated fibroblasts and squamous carcinoma cells through interleukin-1alpha induces cancer progression. Neoplasia. (2014) 16:928–38. 10.1016/j.neo.2014.09.003
    1. Huang YH, Chang CY, Kuo YZ, Fang WY, Kao HY, Tsai ST, et al. . Cancer-associated fibroblast-derived interleukin-1β activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer. Cancer Sci. (2019) 110:2783–93. 10.1111/cas.14135
    1. Liss C, Fekete MJ, Hasina R, Lam CD, Lingen MW. Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages. Int J Cancer. (2001) 93:781–5. 10.1002/ijc.1407
    1. Hakelius M, Koskela A, Reyhani V, Ivarsson M, Grenman R, Rubin K, et al. . Interleukin-1-mediated effects of normal oral keratinocytes and head and neck squamous carcinoma cells on extracellular matrix related gene expression in fibroblasts. Oral Oncol. (2012) 48:1236–41. 10.1016/j.oraloncology.2012.06.013
    1. Glogauer JE, Sun CX, Bradley G, Magalhaes MA. Neutrophils Increase Oral Squamous Cell Carcinoma Invasion through an Invadopodia-Dependent Pathway. Cancer Immunol Res. (2015) 3:1218–26. 10.1158/2326-6066.CIR-15-0017
    1. Wei LY, Lee JJ, Yeh CY, Yang CJ, Kok SH, Ko JY, et al. . Reciprocal activation of cancer-associated fibroblasts and oral squamous carcinoma cells through CXCL1. Oral Oncol. (2019) 88:115–23. 10.1016/j.oraloncology.2018.11.002
    1. Alcolea S, Antón R, Camacho M, Soler M, Alfranca A, Avilés-Jurado FX, et al. . Interaction between head and neck squamous cell carcinoma cells and fibroblasts in the biosynthesis of PGE2. J Lipid Res. (2012) 53:630–42. 10.1194/jlr.M019695
    1. Morita Y, Morita N, Hata K, Nakanishi M, Kimoto N, Omata T, et al. . Cyclooxygenase-2 expression is associated with vascular endothelial growth factor-c and lymph node metastasis in human oral tongue cancer. Oral Surg Oral Med Oral Pathol Oral Radiol. (2014) 117:502–10. 10.1016/j.oooo.2013.12.410
    1. St John MA, Dohadwala M, Luo J, Wang G, Lee G, Shih H, et al. . Proinflammatory mediators upregulate snail in head and neck squamous cell carcinoma. Clin Cancer Res. (2009) 15:6018–27. 10.1158/1078-0432.CCR-09-0011
    1. Yang B, Jia L, Guo Q, Ren H, Hu Y, Xie T. Clinicopathological and prognostic significance of cyclooxygenase-2 expression in head and neck cancer: A meta-analysis. Oncotarget. (2016) 7:47265–77. 10.18632/oncotarget.10059
    1. Lee MK, Park JH, Gi SH, Hwang YS. IL-1β Induces Fascin Expression and Increases Cancer Invasion. Anticancer Res. (2018) 38:6127–32. 10.21873/anticanres.12964
    1. Dong GW, Do NY, Lim SC. Relation between proinflammatory mediators and epithelial-mesenchymal transition in head and neck squamous cell carcinoma. Exp Ther Med. (2010) 1:885–91. 10.3892/etm.2010.124
    1. St John MA. Inflammatory mediators drive metastasis and drug resistance in head and neck squamous cell carcinoma. Laryngoscope. (2015) 125 Suppl 3:S1–11. 10.1002/lary.24998
    1. Lee CH, Wong TS, Chan JY, Lu SC, Lin P, Cheng AJ, et al. . Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma. J Pathol. (2013) 230:298–309. 10.1002/path.4173
    1. Alevizos I, Mahadevappa M, Zhang X, Ohyama H, Kohno Y, Posner M, et al. . Oral cancer in vivo gene expression profiling assisted by laser capture microdissection and microarray analysis. Oncogene. (2001) 20:6196–204. 10.1038/sj.onc.1204685
    1. Choi P, Chen C. Genetic expression profiles and biologic pathway alterations in head and neck squamous cell carcinoma. Cancer. (2005) 104:1113–28. 10.1002/cncr.21293
    1. Cromer A, Carles A, Millon R, Ganguli G, Chalmel F, Lemaire F, et al. . Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene. (2004) 23:2484–98. 10.1038/sj.onc.1207345
    1. Leethanakul C, Patel V, Gillespie J, Shillitoe E, Kellman RM, Ensley JF, et al. . Gene expression profiles in squamous cell carcinomas of the oral cavity: use of laser capture microdissection for the construction and analysis of stage-specific cDNA libraries. Oral Oncol. (2000) 36:474–83. 10.1016/S1368-8375(00)00039-7
    1. Schmalbach CE, Chepeha DB, Giordano TJ, Rubin MA, Teknos TN, Bradford CR, et al. . Molecular profiling and the identification of genes associated with metastatic oral cavity/pharynx squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. (2004) 130:295–302. 10.1001/archotol.130.3.295
    1. Whipple ME, Mendez E, Farwell DG, Agoff SN, Chen C. A genomic predictor of oral squamous cell carcinoma. Laryngoscope. (2004) 114:1346–54. 10.1097/00005537-200408000-00006
    1. Lallemant B, Evrard A, Combescure C, Chapuis H, Chambon G, Raynal C, et al. . Clinical relevance of nine transcriptional molecular markers for the diagnosis of head and neck squamous cell carcinoma in tissue and saliva rinse. BMC Cancer. (2009) 9:370. 10.1186/1471-2407-9-370
    1. Koike H, Uzawa K, Nakashima D, Shimada K, Kato Y, Higo M, et al. . Identification of differentially expressed proteins in oral squamous cell carcinoma using a global proteomic approach. Int J Oncol. (2005) 27:59–67. 10.3892/ijo.27.1.59
    1. Böcker U, Damiao A, Holt L, Soo Han D, Jobin C, Panja A, et al. . Differential expression of interleukin 1 receptor antagonist isoforms in human intestinal epithelial cells. Gastroenterology. (1998) 115:1426–38. 10.1016/S0016-5085(98)70021-6
    1. Bates AM, Gomez Hernandez MP, Lanzel EA, Qian F, Brogden KA. Matrix metalloproteinase (MMP) and immunosuppressive biomarker profiles of seven head and neck squamous cell carcinoma (HNSCC) cell lines. Transl Cancer Res. (2018) 7:533–42. 10.21037/tcr.2018.05.09
    1. Tsai MS, Chen WC, Lu CH, Chen MF. The prognosis of head and neck squamous cell carcinoma related to immunosuppressive tumor microenvironment regulated by IL-6 signaling. Oral Oncol. (2019) 91:47–55. 10.1016/j.oraloncology.2019.02.027
    1. Gaba FI, Sheth CC, Veses V. Salivary biomarkers and their efficacies as diagnostic tools for Oral Squamous Cell Carcinoma: Systematic review and meta-analysis. J Oral Pathol Med. (2018) 50:299–307. 10.1111/jop.12791
    1. Rajan A, Gibson-Corley KN, Choi AB, Ofori-Amanfo GK, Ten Eyck P, Espinosa-Cotton M, et al. . Impact of nuclear interleukin-1 alpha and EGFR expression on recurrence and survival outcomes in oral squamous cell carcinomas. J Oncol. (2019) 2019:5859680. 10.1155/2019/5859680
    1. Iizuka N, Hazama S, Hirose K, Abe T, Tokuda N, Fukumoto T, et al. . Interleukin-1 receptor antagonist mRNA expression and the progression of gastric carcinoma. Cancer Lett. (1999) 179–84. 10.1016/S0304-3835(99)00162-7
    1. Fujiwaki R, Iida K, Nakayama K, Kanasaki H, Hata K, Katabuchi H, et al. . Clinical significance of interleukin-1 receptor antagonist in patients with cervical carcinoma. Gynecol Oncol. (2003) 89:77–83. 10.1016/S0090-8258(02)00154-3
    1. Tian Y, Sun Y, Wu J, Xiong Z, Niu F, Li H, et al. . Impact of IL1R1 polymorphisms on the risk of head and neck cancer in Chinese Han population. Gene. (2020) 757:144927. 10.1016/j.gene.2020.144927
    1. Bonne NJ, Wong DT. Salivary biomarker development using genomic, proteomic and metabolomic approaches. Genome Med. (2012) 4:82. 10.1186/gm383
    1. SahebJamee M, Eslami M, AtarbashiMoghadam F, Sarafnejad A. Salivary concentration of TNFα, IL1α, IL6, and IL8 in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. (2008) 13:E292–5.
    1. Kamatani T, Shiogama S, Yoshihama Y, Kondo S, Shirota T, Shintani S. Interleukin-1 beta in unstimulated whole saliva is a potential biomarker for oral squamous cell carcinoma. Cytokine. (2013) 64:497–502. 10.1016/j.cyto.2013.08.011
    1. Shan J, Sun Z, Yang J, Xu J, Shi W, Wu Y, et al. . Discovery and preclinical validation of proteomic biomarkers in saliva for early detection of oral squamous cell carcinomas. Oral Dis. (2019) 25:97–107. 10.1111/odi.12971
    1. Brailo V, Vucicevic-Boras V, Lukac J, Biocina-Lukenda D, Zilic-Alajbeg I, Milenovic A, et al. . Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer. Med Oral Patol Oral Cir Bucal. (2012) 17:e10–5. 10.4317/medoral.17323
    1. Arellano-Garcia ME, Hu S, Wang J, Henson B, Zhou H, Chia D, et al. . Multiplexed immunobead-based assay for detection of oral cancer protein biomarkers in saliva. Oral Dis. (2008) 14:705–12. 10.1111/j.1601-0825.2008.01488.x
    1. Lee LT, Wong YK, Hsiao HY, Wang YW, Chan MY, Chang KW. Evaluation of saliva and plasma cytokine biomarkers in patients with oral squamous cell carcinoma. Int J Oral Maxillofac Surg. (2018) 47:699–707. 10.1016/j.ijom.2017.09.016
    1. Singh P, Verma JK, Singh JK. Validation of salivary markers, IL-1β, IL-8 and Lgals3bp for detection of oral squamous cell carcinoma in an Indian population. Sci Rep. (2020) 10:7365. 10.1038/s41598-020-64494-3
    1. Brinkmann O, Kastratovic DA, Dimitrijevic MV, Konstantinovic VS, Jelovac DB, Antic J, et al. . Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population. Oral Oncol. (2011) 47:51–5. 10.1016/j.oraloncology.2010.10.009
    1. Val M, Sidoti Pinto GA, Manini L, Gandolfo S, Pentenero M. Variations of salivary concentration of cytokines and chemokines in presence of oral squamous cell carcinoma. A case-crossover longitudinal prospective study. Cytokine. (2019) 120:62–5. 10.1016/j.cyto.2019.04.009
    1. Korostoff A, Reder L, Masood R, Sinha UK. The role of salivary cytokine biomarkers in tongue cancer invasion and mortality. Oral Oncol. (2011) 47:282–7. 10.1016/j.oraloncology.2011.02.006
    1. Boldrup L, Coates P, Gu X, Wang L, Fåhraeus R, Wilms T, et al. . Low potential of circulating interleukin 1 receptor antagonist as a prediction marker for squamous cell carcinoma of the head and neck. J Oral Pathol Med. (2021) 10.1111/jop.13187
    1. Tobón-Arroyave SI, Jaramillo-González PE, Isaza-Guzmán DM. Correlation between salivary IL-1beta levels and periodontal clinical status. Arch Oral Biol. (2008) 53:346–52. 10.1016/j.archoralbio.2007.11.005
    1. Rhodus NL, Cheng B, Bowles W, Myers S, Miller L, Ondrey F. Proinflammatory cytokine levels in saliva before and after treatment of (erosive) oral lichen planus with dexamethasone. Oral Dis. (2006) 12:112–6. 10.1111/j.1601-0825.2005.01165.x
    1. Dinarello CA. Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev. (2010) 29:317–29. 10.1007/s10555-010-9229-0
    1. La E, Fischer SM. Transcriptional regulation of intracellular IL-1 receptor antagonist gene by IL-1 in primary mouse keratinocytes. J Immunol. (2001) 166:6149–55. 10.4049/jimmunol.166.10.6149
    1. Gong Z, Ma J, Su H, Guo T, Cai H, Chen Q, et al. . Interleukin-1 receptor antagonist inhibits angiogenesis in gastric cancer. Int J Clin Oncol. (2018) 23:659–70. 10.1007/s10147-018-1242-2
    1. Holen I, Lefley DV, Francis SE, Rennicks S, Bradbury S, Coleman RE, et al. . IL-1 drives breast cancer growth and bone metastasis in vivo, Oncotarget. (2016) 7:75571–84. 10.18632/oncotarget.12289
    1. Ma J, Sun X, Guo T, Su H, Chen Q, Gong Z, et al. . Interleukin-1 receptor antagonist inhibits angiogenesis via blockage IL-1alpha/PI3K/NF-kappabeta pathway in human colon cancer cell. Cancer Manag Res. (2017) 9:481–93. 10.2147/CMAR.S147699
    1. Lust JA, Lacy MQ, Zeldenrust SR, Witzig TE, Moon-Tasson LL, Dinarello CA, et al. . Reduction in C-reactive protein indicates successful targeting of the IL-1/IL-6 axis resulting in improved survival in early stage multiple myeloma. Am J Hematol. (2016) 91:571–4. 10.1002/ajh.24352
    1. Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, et al. . Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation. (2008) 117:2670–83. 10.1161/CIRCULATIONAHA.107.740233
    1. Stanam A, Gibson-Corley KN, Love-Homan L, Ihejirika N, Simons AL. Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma. Oncotarget. (2016) 7:76087–100. 10.18632/oncotarget.12590

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner