Tumour necrosis factor-α regulates human eosinophil apoptosis via ligation of TNF-receptor 1 and balance between NF-κB and AP-1
Hannu Kankaanranta, Pinja Ilmarinen, Xianzhi Zhang, Ian M Adcock, Aleksi Lahti, Peter J Barnes, Mark A Giembycz, Mark A Lindsay, Eeva Moilanen, Hannu Kankaanranta, Pinja Ilmarinen, Xianzhi Zhang, Ian M Adcock, Aleksi Lahti, Peter J Barnes, Mark A Giembycz, Mark A Lindsay, Eeva Moilanen
Abstract
Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-α on eosinophil apoptosis was reversed by a TNF-α neutralising antibody. The anti-apoptotic effect of TNF-α was not due to autocrine release of known survival-prolonging cytokines interleukins 3 and 5 or granulocyte-macrophage-colony-stimulating factor as their neutralisation did not affect the effect of TNF-α. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-α induced phosphorylation and degradation of IκB and an increase in NF-κB DNA-binding activity. The survival-prolonging effect of TNF-α was reversed by inhibitors of NF-κB pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of IκB kinase, BMS-345541. TNF-α induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-α was potentiated by inhibitors of AP-1, SR 11302 and tanshinone IIA and by an inhibitor of c-jun-N-terminal kinase, SP600125, which is an upstream kinase activating AP-1. Our results thus suggest that TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
![Figure 1. Effect of TNF-α on apoptosis…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g001.jpg)
![Figure 2. Effect of Fas on apoptosis…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g002.jpg)
![Figure 3. Effect of TNF-receptor antibodies on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g003.jpg)
![Figure 4. Effect of TNF-α on IκBα…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g004.jpg)
Figure 5. Effect of TNF-α on IκB…
Figure 5. Effect of TNF-α on IκB expression and NF-κB DNA binding.
In (A) is…
Figure 6. Effect of NF-κB inhibitors on…
Figure 6. Effect of NF-κB inhibitors on apoptosis of human eosinophils in the presence of…
Figure 7. Effect of TNF-α on AP-1…
Figure 7. Effect of TNF-α on AP-1 activation in human eosinophils.
The effect of TNF-α…
Figure 8. Effect of inhibitors of c-jun-N-terminal…
Figure 8. Effect of inhibitors of c-jun-N-terminal kinase and AP-1 on apoptosis of human eosinophils…
- Allergen activates peripheral blood eosinophil nuclear factor-kappaB to generate granulocyte macrophage-colony stimulating factor, tumour necrosis factor-alpha and interleukin-8.Coward WR, Sagara H, Wilson SJ, Holgate ST, Church MK. Coward WR, et al. Clin Exp Allergy. 2004 Jul;34(7):1071-8. doi: 10.1111/j.1365-2222.2004.02003.x. Clin Exp Allergy. 2004. PMID: 15248852
- Inhibitors of both nuclear factor-kappaB and activator protein-1 activation block the neoplastic transformation response.Li JJ, Westergaard C, Ghosh P, Colburn NH. Li JJ, et al. Cancer Res. 1997 Aug 15;57(16):3569-76. Cancer Res. 1997. PMID: 9270030
- Inhibition of nuclear factor-kappaB activation un-masks the ability of TNF-alpha to induce human eosinophil apoptosis.Fujihara S, Ward C, Dransfield I, Hay RT, Uings IJ, Hayes B, Farrow SN, Haslett C, Rossi AG. Fujihara S, et al. Eur J Immunol. 2002 Feb;32(2):457-66. doi: 10.1002/1521-4141(200202)32:23.0.CO;2-1. Eur J Immunol. 2002. PMID: 11813164
- Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation.Tse AK, Wan CK, Shen XL, Yang M, Fong WF. Tse AK, et al. Biochem Pharmacol. 2005 Nov 15;70(10):1443-57. doi: 10.1016/j.bcp.2005.08.011. Epub 2005 Sep 21. Biochem Pharmacol. 2005. PMID: 16181613
- IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1, and apoptosis.Manna SK, Aggarwal BB. Manna SK, et al. J Immunol. 1998 Sep 15;161(6):2863-72. J Immunol. 1998. PMID: 9743347
- Pathogenesis of allergic diseases and implications for therapeutic interventions.Wang J, Zhou Y, Zhang H, Hu L, Liu J, Wang L, Wang T, Zhang H, Cong L, Wang Q. Wang J, et al. Signal Transduct Target Ther. 2023 Mar 24;8(1):138. doi: 10.1038/s41392-023-01344-4. Signal Transduct Target Ther. 2023. PMID: 36964157 Free PMC article. Review.
- Dipotassium Glycyrrhizininate Improves Skin Wound Healing by Modulating Inflammatory Process.Leite CDS, Bonafé GA, Pires OC, Santos TWD, Pereira GP, Pereira JA, Rocha T, Martinez CAR, Ortega MM, Ribeiro ML. Leite CDS, et al. Int J Mol Sci. 2023 Feb 14;24(4):3839. doi: 10.3390/ijms24043839. Int J Mol Sci. 2023. PMID: 36835248 Free PMC article.
- c-FLIP protects eosinophils from TNF-α-mediated cell death in vivo.Gordy C, Liang J, Pua H, He YW. Gordy C, et al. PLoS One. 2014 Oct 21;9(10):e107724. doi: 10.1371/journal.pone.0107724. eCollection 2014. PLoS One. 2014. PMID: 25333625 Free PMC article.
-
- Wenzel SE (2009) Eosinophils in asthma – closing the loop or opening the door? N Engl J Med 360: 1026–1028. - PubMed
-
- Watt AP, Schock BC, Ennis M (2005) Neutrophils and eosinophils: clinical implications of their appearance, presence and disappearance in asthma and COPD. Curr Drug Targets Inflamm Allergy 4: 415–23. - PubMed
-
- Kankaanranta H, Moilanen E, Zhang X (2005) Pharmacological regulation of human eosinophil apoptosis. Curr Drug Targets Inflamm Allergy 4: 433–45. - PubMed
-
- Simon H-U (2009) Cell death in allergic diseases. Apoptosis 14: 439–446. - PubMed
- Research Support, Non-U.S. Gov't
- Antibodies / pharmacology
- Apoptosis / drug effects
- Asthma / genetics*
- Asthma / metabolism
- Asthma / pathology
- Cell Survival / drug effects
- Eosinophils / drug effects
- Eosinophils / metabolism*
- Eosinophils / pathology
- Gene Expression Regulation
- Gliotoxin / pharmacology
- Humans
- I-kappa B Kinase / antagonists & inhibitors
- I-kappa B Kinase / genetics
- I-kappa B Kinase / metabolism
- Imidazoles / pharmacology
- NF-kappa B / antagonists & inhibitors
- NF-kappa B / genetics*
- NF-kappa B / metabolism
- Phosphorylation
- Primary Cell Culture
- Protein Binding
- Pyrrolidines / pharmacology
- Quinoxalines / pharmacology
- Receptors, Tumor Necrosis Factor, Type I / genetics
- Receptors, Tumor Necrosis Factor, Type I / metabolism*
- Retinoids / pharmacology
- Signal Transduction
- Thiocarbamates / pharmacology
- Transcription Factor AP-1 / antagonists & inhibitors
- Transcription Factor AP-1 / genetics*
- Transcription Factor AP-1 / metabolism
- Tumor Necrosis Factor-alpha / antagonists & inhibitors
- Tumor Necrosis Factor-alpha / pharmacology*
- fas Receptor / pharmacology
- 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
- Antibodies
- FAS protein, human
- Imidazoles
- NF-kappa B
- Pyrrolidines
- Quinoxalines
- Receptors, Tumor Necrosis Factor, Type I
- Retinoids
- SR 11302
- Thiocarbamates
- Transcription Factor AP-1
- Tumor Necrosis Factor-alpha
- fas Receptor
- pyrrolidine dithiocarbamic acid
- Gliotoxin
- I-kappa B Kinase
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 5. Effect of TNF-α on IκB…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g005.jpg)
Figure 6. Effect of NF-κB inhibitors on…
Figure 6. Effect of NF-κB inhibitors on apoptosis of human eosinophils in the presence of…
Figure 7. Effect of TNF-α on AP-1…
Figure 7. Effect of TNF-α on AP-1 activation in human eosinophils.
The effect of TNF-α…
Figure 8. Effect of inhibitors of c-jun-N-terminal…
Figure 8. Effect of inhibitors of c-jun-N-terminal kinase and AP-1 on apoptosis of human eosinophils…
- Allergen activates peripheral blood eosinophil nuclear factor-kappaB to generate granulocyte macrophage-colony stimulating factor, tumour necrosis factor-alpha and interleukin-8.Coward WR, Sagara H, Wilson SJ, Holgate ST, Church MK. Coward WR, et al. Clin Exp Allergy. 2004 Jul;34(7):1071-8. doi: 10.1111/j.1365-2222.2004.02003.x. Clin Exp Allergy. 2004. PMID: 15248852
- Inhibitors of both nuclear factor-kappaB and activator protein-1 activation block the neoplastic transformation response.Li JJ, Westergaard C, Ghosh P, Colburn NH. Li JJ, et al. Cancer Res. 1997 Aug 15;57(16):3569-76. Cancer Res. 1997. PMID: 9270030
- Inhibition of nuclear factor-kappaB activation un-masks the ability of TNF-alpha to induce human eosinophil apoptosis.Fujihara S, Ward C, Dransfield I, Hay RT, Uings IJ, Hayes B, Farrow SN, Haslett C, Rossi AG. Fujihara S, et al. Eur J Immunol. 2002 Feb;32(2):457-66. doi: 10.1002/1521-4141(200202)32:23.0.CO;2-1. Eur J Immunol. 2002. PMID: 11813164
- Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation.Tse AK, Wan CK, Shen XL, Yang M, Fong WF. Tse AK, et al. Biochem Pharmacol. 2005 Nov 15;70(10):1443-57. doi: 10.1016/j.bcp.2005.08.011. Epub 2005 Sep 21. Biochem Pharmacol. 2005. PMID: 16181613
- IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1, and apoptosis.Manna SK, Aggarwal BB. Manna SK, et al. J Immunol. 1998 Sep 15;161(6):2863-72. J Immunol. 1998. PMID: 9743347
- Pathogenesis of allergic diseases and implications for therapeutic interventions.Wang J, Zhou Y, Zhang H, Hu L, Liu J, Wang L, Wang T, Zhang H, Cong L, Wang Q. Wang J, et al. Signal Transduct Target Ther. 2023 Mar 24;8(1):138. doi: 10.1038/s41392-023-01344-4. Signal Transduct Target Ther. 2023. PMID: 36964157 Free PMC article. Review.
- Dipotassium Glycyrrhizininate Improves Skin Wound Healing by Modulating Inflammatory Process.Leite CDS, Bonafé GA, Pires OC, Santos TWD, Pereira GP, Pereira JA, Rocha T, Martinez CAR, Ortega MM, Ribeiro ML. Leite CDS, et al. Int J Mol Sci. 2023 Feb 14;24(4):3839. doi: 10.3390/ijms24043839. Int J Mol Sci. 2023. PMID: 36835248 Free PMC article.
- c-FLIP protects eosinophils from TNF-α-mediated cell death in vivo.Gordy C, Liang J, Pua H, He YW. Gordy C, et al. PLoS One. 2014 Oct 21;9(10):e107724. doi: 10.1371/journal.pone.0107724. eCollection 2014. PLoS One. 2014. PMID: 25333625 Free PMC article.
-
- Wenzel SE (2009) Eosinophils in asthma – closing the loop or opening the door? N Engl J Med 360: 1026–1028. - PubMed
-
- Watt AP, Schock BC, Ennis M (2005) Neutrophils and eosinophils: clinical implications of their appearance, presence and disappearance in asthma and COPD. Curr Drug Targets Inflamm Allergy 4: 415–23. - PubMed
-
- Kankaanranta H, Moilanen E, Zhang X (2005) Pharmacological regulation of human eosinophil apoptosis. Curr Drug Targets Inflamm Allergy 4: 433–45. - PubMed
-
- Simon H-U (2009) Cell death in allergic diseases. Apoptosis 14: 439–446. - PubMed
- Research Support, Non-U.S. Gov't
- Antibodies / pharmacology
- Apoptosis / drug effects
- Asthma / genetics*
- Asthma / metabolism
- Asthma / pathology
- Cell Survival / drug effects
- Eosinophils / drug effects
- Eosinophils / metabolism*
- Eosinophils / pathology
- Gene Expression Regulation
- Gliotoxin / pharmacology
- Humans
- I-kappa B Kinase / antagonists & inhibitors
- I-kappa B Kinase / genetics
- I-kappa B Kinase / metabolism
- Imidazoles / pharmacology
- NF-kappa B / antagonists & inhibitors
- NF-kappa B / genetics*
- NF-kappa B / metabolism
- Phosphorylation
- Primary Cell Culture
- Protein Binding
- Pyrrolidines / pharmacology
- Quinoxalines / pharmacology
- Receptors, Tumor Necrosis Factor, Type I / genetics
- Receptors, Tumor Necrosis Factor, Type I / metabolism*
- Retinoids / pharmacology
- Signal Transduction
- Thiocarbamates / pharmacology
- Transcription Factor AP-1 / antagonists & inhibitors
- Transcription Factor AP-1 / genetics*
- Transcription Factor AP-1 / metabolism
- Tumor Necrosis Factor-alpha / antagonists & inhibitors
- Tumor Necrosis Factor-alpha / pharmacology*
- fas Receptor / pharmacology
- 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
- Antibodies
- FAS protein, human
- Imidazoles
- NF-kappa B
- Pyrrolidines
- Quinoxalines
- Receptors, Tumor Necrosis Factor, Type I
- Retinoids
- SR 11302
- Thiocarbamates
- Transcription Factor AP-1
- Tumor Necrosis Factor-alpha
- fas Receptor
- pyrrolidine dithiocarbamic acid
- Gliotoxin
- I-kappa B Kinase
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 6. Effect of NF-κB inhibitors on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g006.jpg)
Figure 7. Effect of TNF-α on AP-1…
Figure 7. Effect of TNF-α on AP-1 activation in human eosinophils.
The effect of TNF-α…
Figure 8. Effect of inhibitors of c-jun-N-terminal…
Figure 8. Effect of inhibitors of c-jun-N-terminal kinase and AP-1 on apoptosis of human eosinophils…
- Allergen activates peripheral blood eosinophil nuclear factor-kappaB to generate granulocyte macrophage-colony stimulating factor, tumour necrosis factor-alpha and interleukin-8.Coward WR, Sagara H, Wilson SJ, Holgate ST, Church MK. Coward WR, et al. Clin Exp Allergy. 2004 Jul;34(7):1071-8. doi: 10.1111/j.1365-2222.2004.02003.x. Clin Exp Allergy. 2004. PMID: 15248852
- Inhibitors of both nuclear factor-kappaB and activator protein-1 activation block the neoplastic transformation response.Li JJ, Westergaard C, Ghosh P, Colburn NH. Li JJ, et al. Cancer Res. 1997 Aug 15;57(16):3569-76. Cancer Res. 1997. PMID: 9270030
- Inhibition of nuclear factor-kappaB activation un-masks the ability of TNF-alpha to induce human eosinophil apoptosis.Fujihara S, Ward C, Dransfield I, Hay RT, Uings IJ, Hayes B, Farrow SN, Haslett C, Rossi AG. Fujihara S, et al. Eur J Immunol. 2002 Feb;32(2):457-66. doi: 10.1002/1521-4141(200202)32:23.0.CO;2-1. Eur J Immunol. 2002. PMID: 11813164
- Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation.Tse AK, Wan CK, Shen XL, Yang M, Fong WF. Tse AK, et al. Biochem Pharmacol. 2005 Nov 15;70(10):1443-57. doi: 10.1016/j.bcp.2005.08.011. Epub 2005 Sep 21. Biochem Pharmacol. 2005. PMID: 16181613
- IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1, and apoptosis.Manna SK, Aggarwal BB. Manna SK, et al. J Immunol. 1998 Sep 15;161(6):2863-72. J Immunol. 1998. PMID: 9743347
- Pathogenesis of allergic diseases and implications for therapeutic interventions.Wang J, Zhou Y, Zhang H, Hu L, Liu J, Wang L, Wang T, Zhang H, Cong L, Wang Q. Wang J, et al. Signal Transduct Target Ther. 2023 Mar 24;8(1):138. doi: 10.1038/s41392-023-01344-4. Signal Transduct Target Ther. 2023. PMID: 36964157 Free PMC article. Review.
- Dipotassium Glycyrrhizininate Improves Skin Wound Healing by Modulating Inflammatory Process.Leite CDS, Bonafé GA, Pires OC, Santos TWD, Pereira GP, Pereira JA, Rocha T, Martinez CAR, Ortega MM, Ribeiro ML. Leite CDS, et al. Int J Mol Sci. 2023 Feb 14;24(4):3839. doi: 10.3390/ijms24043839. Int J Mol Sci. 2023. PMID: 36835248 Free PMC article.
- c-FLIP protects eosinophils from TNF-α-mediated cell death in vivo.Gordy C, Liang J, Pua H, He YW. Gordy C, et al. PLoS One. 2014 Oct 21;9(10):e107724. doi: 10.1371/journal.pone.0107724. eCollection 2014. PLoS One. 2014. PMID: 25333625 Free PMC article.
-
- Wenzel SE (2009) Eosinophils in asthma – closing the loop or opening the door? N Engl J Med 360: 1026–1028. - PubMed
-
- Watt AP, Schock BC, Ennis M (2005) Neutrophils and eosinophils: clinical implications of their appearance, presence and disappearance in asthma and COPD. Curr Drug Targets Inflamm Allergy 4: 415–23. - PubMed
-
- Kankaanranta H, Moilanen E, Zhang X (2005) Pharmacological regulation of human eosinophil apoptosis. Curr Drug Targets Inflamm Allergy 4: 433–45. - PubMed
-
- Simon H-U (2009) Cell death in allergic diseases. Apoptosis 14: 439–446. - PubMed
- Research Support, Non-U.S. Gov't
- Antibodies / pharmacology
- Apoptosis / drug effects
- Asthma / genetics*
- Asthma / metabolism
- Asthma / pathology
- Cell Survival / drug effects
- Eosinophils / drug effects
- Eosinophils / metabolism*
- Eosinophils / pathology
- Gene Expression Regulation
- Gliotoxin / pharmacology
- Humans
- I-kappa B Kinase / antagonists & inhibitors
- I-kappa B Kinase / genetics
- I-kappa B Kinase / metabolism
- Imidazoles / pharmacology
- NF-kappa B / antagonists & inhibitors
- NF-kappa B / genetics*
- NF-kappa B / metabolism
- Phosphorylation
- Primary Cell Culture
- Protein Binding
- Pyrrolidines / pharmacology
- Quinoxalines / pharmacology
- Receptors, Tumor Necrosis Factor, Type I / genetics
- Receptors, Tumor Necrosis Factor, Type I / metabolism*
- Retinoids / pharmacology
- Signal Transduction
- Thiocarbamates / pharmacology
- Transcription Factor AP-1 / antagonists & inhibitors
- Transcription Factor AP-1 / genetics*
- Transcription Factor AP-1 / metabolism
- Tumor Necrosis Factor-alpha / antagonists & inhibitors
- Tumor Necrosis Factor-alpha / pharmacology*
- fas Receptor / pharmacology
- 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
- Antibodies
- FAS protein, human
- Imidazoles
- NF-kappa B
- Pyrrolidines
- Quinoxalines
- Receptors, Tumor Necrosis Factor, Type I
- Retinoids
- SR 11302
- Thiocarbamates
- Transcription Factor AP-1
- Tumor Necrosis Factor-alpha
- fas Receptor
- pyrrolidine dithiocarbamic acid
- Gliotoxin
- I-kappa B Kinase
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 7. Effect of TNF-α on AP-1…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g007.jpg)
![Figure 8. Effect of inhibitors of c-jun-N-terminal…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3938678/bin/pone.0090298.g008.jpg)
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Source: PubMed