Peroxisome proliferator-activated receptors alpha and gamma down-regulate allergic inflammation and eosinophil activation

Gaetane Woerly, Kohei Honda, Marc Loyens, Jean-Paul Papin, Johan Auwerx, Bart Staels, Monique Capron, David Dombrowicz, Gaetane Woerly, Kohei Honda, Marc Loyens, Jean-Paul Papin, Johan Auwerx, Bart Staels, Monique Capron, David Dombrowicz

Abstract

Allergic asthma is characterized by airway hyperresponsiveness, eosinophilia, and mucus accumulation and is associated with increased IgE concentrations. We demonstrate here that peroxisome proliferator-activated receptors (PPARs), PPAR-alpha and PPAR-gamma, which have been shown recently to be involved in the regulation of various cell types within the immune system, decrease antigen-induced airway hyperresponsiveness, lung inflammation, eosinophilia, cytokine production, and GATA-3 expression as well as serum levels of antigen-specific IgE in a murine model of human asthma. In addition, we demonstrate that PPAR-alpha and -gamma are expressed in eosinophils and their activation inhibits in vitro chemotaxis and antibody-dependent cellular cytotoxicity. Thus, PPAR-alpha and -gamma (co)agonists might be of therapeutic interest for the regulation of allergic or inflammatory reactions by targeting both regulatory and effector cells involved in the immune response.

Figures

Figure 1.
Figure 1.
Increased asthma-like reactions in PPAR-α−/− mice. (a) AHR of OVA-sensitized and -challenged or unsensitized but challenged PPAR-α−/− or corresponding WT animals to increasing methacholine concentrations 48 h after the last OVA nebulization. (b) Cellularity and eosinophilia in BALs at the time of sacrifice. (n = 4–13 animals per group. Data expressed as mean ± SEM; some bars may fall within mark). §, Statistically different from OVA-sensitized and aerosol-challenged WT animals. +, Statistically different from unsensitized but aerosol challenged PPAR-α−/− mice. $, Statistically different from unsensitized but aerosol challenged WT mice (see Table I for P values). (c–f) May Grünwald Giemsa staining of lung sections from OVA-sensitized and aerosol-challenged (c and d) or unsensitized but aerosol-challenged (e and f) PPAR-α−/− (c and e) or WT (d and f) mice (original magnification 100). Inset: arrows indicate eosinophils (original magnification 400).
Figure 2.
Figure 2.
Increased lung inflammation and humoral response in PPAR-α−/− mice. (a) Serum OVA-specific IgE (left) and IgG1 (right) from animals treated as in Fig. 1 24 h after the last OVA nebulization. (b) IL-6, -13, and eotaxin content from lung extracts from animals treated as in Fig. 1. (n = 4–13 animals per group. Data expressed as mean ± SEM; some bars may fall within mark.) §, Statistically different from OVA-sensitized and aerosol-challenged WT animals. +, Statistically different from unsensitized but aerosol-challenged PPAR-α−/− mice. $, Statistically different from unsensitized but aerosol-challenged WT mice (see Table I for P values). (c) Western blot analysis of GATA-3 expression in lung extracts (and lymph nodes [L. Node]) from individual animals treated as in Fig. 1.
Figure 3.
Figure 3.
Regulation of asthma-like reactions by PPAR-γ. Mice were sensitized by intraperitoneal injection of OVA in alum and challenged by repeated nebulizations of OVA together with nebulization with 5 × 10−5 M ciglitazone, 5 × 10−5 M ciglitazone and 5 × 10−5 M GW9662 or vehicle. Unsensitized control animals received alum only and were challenged with OVA as for sensitized animals. (a) AHR to increasing methacholine concentrations 48 h after the last nebulization. (b) Cellularity and eosinophilia in BALs at the time of sacrifice. (n = 4–8 animals per group; data expressed as mean ± SEM, some bars may fall within mark). §: Statistically different from OVA-sensitized and aerosol-challenged animals. +: Statistically different from OVA-sensitized and aerosol-challenged mice treated with both ciglitazone and GW9662. $: Statistically different from unsensitized but aerosol challenged mice (see Table I for P values). (c) May Grünwald Giemsa staining of lung sections from sensitized mice nebulized with OVA together with vehicle (upper left), with 5 × 10−5 M ciglitazone (upper right) or with 5 × 10−5 M ciglitazone and 5 × 10−5 M GW9662 (lower left) and from unsensitized animals (lower right) (original magnification 100).
Figure 4.
Figure 4.
Regulation of pulmonary inflammation and humoral response by PPAR-γ. (a) Serum OVA-specific IgE (left) and IgG1 (right) from animals treated as in Fig. 3 24 h after the last OVA nebulization. (b) IL-4, -5, -6, and -13 content of lung extracts from animals treated as in Fig. 3. (n = 4–19 animals per group. Data expressed as mean ± SEM; some bars may fall within mark.) §, Statistically different from OVA-sensitized and aerosol-challenged animals. +, Statistically different from OVA-sensitized and aerosol-challenged mice treated with both ciglitazone and GW9662. $, Statistically different from unsensitized but aerosol-challenged mice (see Table I for P values). (c) Western blot analysis of GATA-3 expression in lung extracts (and lymph nodes [L. Node]) from individual animals treated as in Fig. 3.
Figure 5.
Figure 5.
PPAR expression in eosinophils. (a) RT-PCR amplification of PPAR-α (top), PPAR-γ (middle), and β-actin (bottom) mRNA from human, mouse, and rat eosinophils. (top) Total WT mouse liver, rat peritoneal eosinophils, and eosinophils from IL-5 Tg mouse spleen (amplicon size: 215 bp; left). HepG2 cells and human peripheral blood eosinophils (amplicon size: 304 bp; right). (middle) Total WT mouse spleen and eosinophils from IL-5 Tg mouse spleen (amplicon size: 473 bp; left). Total rat spleen and rat peritoneal eosinophils (amplicon size: 343 bp; center). HepG2 cells and human peripheral blood eosinophils (amplicon size: 337 bp; right). (bottom) Total WT mouse spleen, eosinophils from IL-5 Tg mouse spleen, total WT mouse liver, total rat spleen, and peritoneal rat eosinophils (amplicon size: 532 bp; left). Human peripheral blood eosinophils and HepG2 cells (amplicon size: 238 bp; right). (b) Identification of PPAR-α (top) and PPAR-γ (bottom) proteins in human and mouse eosinophil lysates by Western blot analysis. Immunodetection of PPAR-α and PPAR-γ in cell lysates from IL-5 Tg mouse eosinophils and WT mouse liver or human peripheral blood eosinophils from two different donors and adipose tissue after SDS-PAGE and transfer on membrane. (c) Detection of PPAR-α and PPAR-γ by flow cytometry on permeabilized human (top), mouse (bottom left), and rat eosinophils (bottom right). Relative expression levels of PPAR-α and PPAR-γ in eosinophils from eight donors with hypereosinophilia (mean fluorescence intensity [MFI]; control rabbit IgG (rbIgG); average value is represented by the horizontal bar in each group). On histogram plots, anti–PPAR-α (thin line), anti–PPAR-γ (thick line), control rabbit IgG (dotted line), and FITC-conjugated secondary antibody (dashed line).
Figure 6.
Figure 6.
Regulation of eosinophil function by PPAR in vitro. (a and b) Inhibition of eosinophil chemotaxis by PPAR. Dose-dependent inhibition of IL-5– and eotaxin-induced chemotaxis of human peripheral blood eosinophils by rosiglitazone (a) and WY14653 (b). P −5 M). (c and d) Inhibition of eosinophil-mediated ADCC by PPAR agonists. Dose-dependent inhibition of human (c) or rat (d) eosinophil-mediated ADCC toward S. mansoni larvae by WY14653, ciglitazone, and rosiglitazone (n = 3–8 independent experiments; data expressed as mean ± SEM). (1) and (5) P < 0.0001 for rosiglitazone-treated versus vehicle-treated cells; (2) P = 0.034 and (6) P < 0.0001 for ciglitazone-treated versus vehicle-treated cells; (3) P = 0.037 and (4) P < 0.0001 for WY14653-treated versus vehicle-treated cells.

References

    1. Wills-Karp, M. 1999. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17:255–281.
    1. Maddox, L., and D.A. Schwartz. 2002. The pathophysiology of asthma. Annu. Rev. Med. 53:477–498.
    1. Dombrowicz, D., and M. Capron. 2001. Eosinophils, allergy and parasites. Curr. Opin. Immunol. 13:716–720.
    1. Desvergne, B., and W. Wahli. 1999. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 20:649–688.
    1. Devchand, P.R., H. Keller, J.M. Peters, M. Vazquez, F.J. Gonzalez, and W. Wahli. 1996. The PPAralpha-leukotriene B4 pathway to inflammation control. Nature. 384:39–43.
    1. Hatae, T., M. Wada, C. Yokoyama, M. Shimonishi, and T. Tanabe. 2001. Prostacyclin-dependent apoptosis mediated by PPARdelta. J. Biol. Chem. 276:46260–46267.
    1. Nagy, L., P. Tontonoz, J.G. Alvarez, H. Chen, and R.M. Evans. 1998. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 93:229–240.
    1. Forman, B.M., P. Tontonoz, J. Chen, R.P. Brun, B.M. Spiegelman, and R.M. Evans. 1995. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 83:803–812.
    1. Delerive, P., J.C. Fruchart, and B. Staels. 2001. Peroxisome proliferator-activated receptors in inflammation control. J. Endocrinol. 169:453–459.
    1. Clark, R.B. 2002. The role of PPARs in inflammation and immunity. J. Leukoc. Biol. 71:388–400.
    1. Daynes, R.A., and D.C. Jones. 2002. Emerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol. 2:748–759.
    1. Clark, R.B., D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S.J. Padula. 2000. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J. Immunol. 164:1364–1371.
    1. Jones, D.C., X. Ding, and R.A. Daynes. 2001. Nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in resting murine lymphocytes: the PPARalpha in T and B lymphocytes is both transactivation and transrepression competent. J. Biol. Chem. 277:6838–6845.
    1. Chinetti, G., S. Griglio, M. Antonucci, I.P. Torra, P. Delerive, Z. Majd, J.C. Fruchart, J. Chapman, J. Najib, and B. Staels. 1998. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem. 273:25573–25580.
    1. Ricote, M., A.C. Li, T.M. Willson, C.J. Kelly, and C.K. Glass. 1998. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 391:79–82.
    1. Tontonoz, P., L. Nagy, J.G. Alvarez, V.A. Thomazy, and R.M. Evans. 1998. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 93:241–252.
    1. Huang, J.T., J.S. Welch, M. Ricote, C.J. Binder, T.M. Willson, C. Kelly, J.L. Witztum, C.D. Funk, D. Conrad, and C.K. Glass. 1999. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature. 400:378–382.
    1. Moore, K.J., E.D. Rosen, M.L. Fitzgerald, F. Randow, L.P. Andersson, D. Altshuler, D.S. Milstone, R.M. Mortensen, B.M. Spiegelman, and M.W. Freeman. 2001. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat. Med. 7:41–47.
    1. Faveeuw, C., S. Fougeray, V. Angeli, J. Fontaine, G. Chinetti, P. Gosset, P. Delerive, C. Maliszewski, M. Capron, B. Staels, et al. 2000. Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett. 486:261–266.
    1. Sugiyama, H., T. Nonaka, T. Kishimoto, K. Komoriya, K. Tsuji, and T. Nakahata. 2000. Peroxisome proliferator-activated receptors are expressed in human cultured mast cells: a possible role of these receptors in negative regulation of mast cell activation. Eur. J. Immunol. 30:3363–3370.
    1. Tan, N.S., L. Michalik, N. Noy, R. Yasmin, C. Pacot, M. Heim, B. Fluhmann, B. Desvergne, and W. Wahli. 2001. Critical roles of PPAR beta/delta in keratinocyte response to inflammation. Genes Dev. 15:3263–3277.
    1. Su, C.G., X. Wen, S.T. Bailey, W. Jiang, S.M. Rangwala, S.A. Keilbaugh, A. Flanigan, S. Murthy, M.A. Lazar, and G.D. Wu. 1999. A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J. Clin. Invest. 104:383–389.
    1. Desreumaux, P., L. Dubuquoy, S. Nutten, M. Peuchmaur, W. Englaro, K. Schoonjans, B. Derijard, B. Desvergne, W. Wahli, P. Chambon, et al. 2001. Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator–activated receptor γ (PPARγ) heterodimer. A basis for new therapeutic strategies. J. Exp. Med. 193:827–838.
    1. Setoguchi, K., Y. Misaki, Y. Terauchi, T. Yamauchi, K. Kawahata, T. Kadowaki, and K. Yamamoto. 2001. Peroxisome proliferator-activated receptor-gamma haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis. J. Clin. Invest. 108:1667–1675.
    1. Lewis, J.D., G.R. Lichtenstein, R.B. Stein, J.J. Deren, T.A. Judge, F. Fogt, E.E. Furth, E.J. Demissie, L.B. Hurd, C.G. Su, et al. 2001. An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis. Am. J. Gastroenterol. 96:3323–3328.
    1. Benayoun, L., S. Letuve, A. Druilhe, J. Boczkowski, M.C. Dombret, P. Mechighel, J. Megret, G. Leseche, M. Aubier, and M. Pretolani. 2001. Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am. J. Respir. Crit. Care Med. 164:1487–1494.
    1. Poynter, M.E., and R.A. Daynes. 1998. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J. Biol. Chem. 273:32833–32841.
    1. Delerive, P., K. De Bosscher, S. Besnard, W. Vanden Berghe, J.M. Peters, F.J. Gonzalez, J.C. Fruchart, A. Tedgui, G. Haegeman, and B. Staels. 1999. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J. Biol. Chem. 274:32048–32054.
    1. Lee, S.S., T. Pineau, J. Drago, E.J. Lee, J.W. Owens, D.L. Kroetz, P.M. Fernandez-Salguero, H. Westphal, and F.J. Gonzalez. 1995. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol. 15:3012–3022.
    1. Kayaba, H., D. Dombrowicz, G. Woerly, J.P. Papin, S. Loiseau, and M. Capron. 2001. Human eosinophils and human high affinity IgE receptor transgenic mouse eosinophils express low levels of high affinity IgE receptor, but release IL-10 upon receptor activation. J. Immunol. 167:995–1003.
    1. Hamelmann, E., J. Schwarze, K. Takeda, A. Oshiba, G.L. Larsen, C.G. Irvin, and E.W. Gelfand. 1997. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156:766–775.
    1. Standiford, T.J., S.L. Kunkel, N.W. Lukacs, M.J. Greenberger, J.M. Danforth, R.G. Kunkel, and R.M. Strieter. 1995. Macrophage inflammatory protein-1 alpha mediates lung leukocyte recruitment, lung capillary leak, and early mortality in murine endotoxemia. J. Immunol. 155:1515–1524.
    1. Angeli, V., C. Faveeuw, P. Delerive, J. Fontaine, Y. Barriera, N. Franchimont, B. Staels, M. Capron, and F. Trottein. 2001. Schistosoma mansoni induces the synthesis of IL-6 in pulmonary microvascular endothelial cells: role of IL-6 in the control of lung eosinophilia during infection. Eur. J. Immunol. 31:2751–2761.
    1. Woerly, G., N. Roger, S. Loiseau, D. Dombrowicz, A. Capron, and M. Capron. 1999. Expression of CD28 and CD86 by human eosinophils and role in the secretion of type 1 cytokines (interleukin 2 and interferon γ): inhibition by immunoglobulin A complexes. J. Exp. Med. 190:487–495.
    1. Huang, W.W., E.A. Garcia-Zepeda, A. Sauty, H.C. Oettgen, M.E. Rothenberg, and A.D. Luster. 1998. Molecular and biological characterization of the murine leukotriene B4 receptor expressed on eosinophils. J. Exp. Med. 188:1063–1074.
    1. Capron, M., S. Loiseau, J.P. Papin, S. Robertson, and A. Capron. 1998. Inhibitory effects of lodoxamide on eosinophil activation. Int. Arch. Allergy Immunol. 116:140–146.
    1. Dombrowicz, D., B. Quatannens, J.P. Papin, A. Capron, and M. Capron. 2000. Expression of a functional Fc epsilon RI on rat eosinophils and macrophages. J. Immunol. 165:1266–1271.
    1. Malm-Erjefalt, M., C.G. Persson, and J.S. Erjefalt. 2001. Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 24:352–359.
    1. Zheng, W., and R.A. Flavell. 1997. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 89:587–596.
    1. Justice, J.P., M.T. Borchers, J.J. Lee, W.H. Rowan, Y. Shibata, and M.R. Van Scott. 2002. Ragweed-induced expression of GATA-3, IL-4, and IL-5 by eosinophils in the lungs of allergic C57BL/6J mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 282:L302–L309.
    1. Capron, M., and A. Capron. 1994. Immunoglobulin E and effector cells in schistosomiasis. Science. 264:1876–1877.
    1. Grezel, D., M. Capron, J.M. Grzych, J. Fontaine, J.P. Lecocq, and A. Capron. 1993. Protective immunity induced in rat schistosomiasis by a single dose of the Sm28GST recombinant antigen: effector mechanisms involving IgE and IgA antibodies. Eur. J. Immunol. 23:454–460.
    1. Gavett, S.H., X. Chen, F. Finkelman, and M. Wills-Karp. 1994. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am. J. Respir. Cell Mol. Biol. 10:587–593.
    1. Hamelmann, E., A. Oshiba, J. Paluh, K. Bradley, J. Loader, T.A. Potter, G.L. Larsen, and E.W. Gelfand. 1996. Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a marine model of airway sensitization. J. Exp. Med. 183:1719–1729.
    1. Foster, P.S., A.W. Mould, M. Yang, J. Mackenzie, J. Mattes, S.P. Hogan, S. Mahalingam, A.N. McKenzie, M.E. Rothenberg, I.G. Young, et al. 2001. Elemental signals regulating eosinophil accumulation in the lung. Immunol. Rev. 179:173–181.
    1. Hart, P.H. 2001. Regulation of the inflammatory response in asthma by mast cell products. Immunol. Cell Biol. 79:149–153.
    1. Jones, D.C., B.M. Manning, and R.A. Daynes. 2002. A role for the peroxisome proliferator-activated receptor alpha in T-cell physiology and ageing immunobiology. Proc. Nutr. Soc. 61:363–369.
    1. Woerly, G., P. Lacy, A.B. Younes, N. Roger, S. Loiseau, R. Moqbel, and M. Capron. 2002. Human eosinophils express and release IL-13 following CD28-dependent activation. J. Leukoc. Biol. 72:769–779.
    1. Mattes, J., M. Yang, S. Mahalingam, J. Kuehr, D.C. Webb, L. Simson, S.P. Hogan, A. Koskinen, A.N. McKenzie, L.A. Dent, et al. 2002. Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J. Exp. Med. 195:1433–1444.
    1. Zhu, Z., R.J. Homer, Z. Wang, Q. Chen, G.P. Geba, J. Wang, Y. Zhang, and J.A. Elias. 1999. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 103:779–788.
    1. Kuperman, D.A., X. Huang, L.L. Koth, G.H. Chang, G.M. Dolganov, Z. Zhu, J.A. Elias, D. Sheppard, and D.J. Erle. 2002. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 8:885–889.
    1. Lee, J.H., N. Kaminski, G. Dolganov, G. Grunig, L. Koth, C. Solomon, D.J. Erle, and D. Sheppard. 2001. Interleukin-13 induces dramatically different transcriptional programs in three human airway cell types. Am. J. Respir. Cell Mol. Biol. 25:474–485.
    1. Rothenberg, M.E., A.D. Luster, and P. Leder. 1995. Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin 4-induced tumor suppression. Proc. Natl. Acad. Sci. USA. 92:8960–8964.
    1. Lee, H., W. Shi, P. Tontonoz, S. Wang, G. Subbanagounder, C.C. Hedrick, S. Hama, C. Borromeo, R.M. Evans, J.A. Berliner, and L. Nagy. 2000. Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells. Circ. Res. 87:516–521.
    1. Wang, A.C., X. Dai, B. Luu, and D.J. Conrad. 2001. Peroxisome proliferator-activated receptor-gamma regulates airway epithelial cell activation. Am. J. Respir. Cell Mol. Biol. 24:688–693.
    1. Patel, H.J., M.G. Belvisi, D. Bishop-Bailey, M.H. Yacoub, and J.A. Mitchell. 2003. Activation of peroxisome proliferator-activated receptors in human airway smooth muscle cells has a superior anti-inflammatory profile to corticosteroids: relevance for chronic obstructive pulmonary disease therapy. J. Immunol. 170:2663–2669.
    1. Gosset, P., A.S. Charbonnier, P. Delerive, J. Fontaine, B. Staels, J. Pestel, A.B. Tonnel, and F. Trottein. 2001. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur. J. Immunol. 31:2857–2865.
    1. Lambrecht, B.N., M. De Veerman, A.J. Coyle, J.C. Gutierrez-Ramos, K. Thielemans, and R.A. Pauwels. 2000. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106:551–559.
    1. Angeli, V., C. Faveeuw, O. Roye, J. Fontaine, E. Teissier, A. Capron, I. Wolowczuk, M. Capron, and F. Trottein. 2001. Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans' cell migration during schistosomiasis infection. J. Exp. Med. 193:1135–1147.
    1. Yang, X.Y., L.H. Wang, T. Chen, D.R. Hodge, J.H. Resau, L. DaSilva, and W.L. Farrar. 2000. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J. Biol. Chem. 275:4541–4544.
    1. Miyazaki, Y., H. Tachibana, and K. Yamada. 2002. Inhibitory effect of peroxisome proliferator-activated receptor-gamma ligands on the expression of IgE heavy chain germline transcripts in the human B cell line DND39. Biochem. Biophys. Res. Commun. 295:547–552.
    1. Adachi, T., and R. Alam. 1998. The mechanism of IL-5 signal transduction. Am. J. Physiol. 275:C623–C633.
    1. Kampen, G.T., S. Stafford, T. Adachi, T. Jinquan, S. Quan, J.A. Grant, P.S. Skov, L.K. Poulsen, and R. Alam. 2000. Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases. Blood. 95:1911–1917.
    1. Tsai, M., S.Y. Tam, and S.J. Galli. 1993. Distinct patterns of early response gene expression and proliferation in mouse mast cells stimulated by stem cell factor, interleukin-3, or IgE and antigen. Eur. J. Immunol. 23:867–872.
    1. Razin, E., Z. Szallasi, M.G. Kazanietz, P.M. Blumberg, and J. Rivera. 1994. Protein kinases C-beta and C-epsilon link the mast cell high-affinity receptor for IgE to the expression of c-fos and c-jun. Proc. Natl. Acad. Sci. USA. 91:7722–7726.
    1. Ishizuka, T., K. Chayama, K. Takeda, E. Hamelmann, N. Terada, G.M. Keller, G.L. Johnson, and E.W. Gelfand. 1999. Mitogen-activated protein kinase activation through Fc epsilon receptor I and stem cell factor receptor is differentially regulated by phosphatidylinositol 3-kinase and calcineurin in mouse bone marrow-derived mast cells. J. Immunol. 162:2087–2094.
    1. Pelletier, C., N. Varin-Blank, J. Rivera, B. Iannascoli, F. Marchand, B. David, A. Weyer, and U. Blank. 1998. Fc epsilonRI-mediated induction of TNF-alpha gene expression in the RBL-2H3 mast cell line: regulation by a novel NF-kappaB-like nuclear binding complex. J. Immunol. 161:4768–4776.
    1. Leckie, M.J., A. ten Brinke, J. Khan, Z. Diamant, B.J. O'Connor, C.M. Walls, A.K. Mathur, H.C. Cowley, K.F. Chung, R. Djukanovic, et al. 2000. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 356:2144–2148.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa