TH1 and TH2 cytokine inhibition by 3,5-bis(trifluoromethyl)pyrazoles,a novel class of immunomodulators |
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Authors: | Chen Yung- Wu Smith Morey L Chiou Grace X Ballaron Stephen Sheets Michael P Gubbins Earl Warrior Usha Wilkins Julie Surowy Carol Nakane Masaki Carter George W Trevillyan James M Mollison Karl Djuric Stevan W |
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Institution: | Immunological Disease Research, AP9 R46R, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA. yung-wu.chen@abbott.com |
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Abstract: | In order to discover novel immunomodulators for application in treating autoimmune diseases, a stable Jurkat transfectant was constructed in which luciferase reporter gene is driven by a full-length IL-2 promotor. A chemical library was screened to identify compounds that inhibited luciferase expression in Jurkat transfectants stimulated with PMA and ionomycin. A class of compounds (bis-trifluoromethyl pyrazole, BTPs) was identified from this screen. BTPs were shown to inhibit anti-CD3 and anti-CD28 antibody-induced IL-2 secretion, mixed lymphocyte reaction, and Con A-induced T cell proliferation in normal human peripheral blood T cells. In addition, mRNA levels of IL-4, IL-5, IL-9, IL-10, IL-13, IL-15, and IFN-gamma were markedly inhibited by BTPs in peripheral blood mononuclear cells stimulated by Con A as determined by multi-probe RNA protection assay. Furthermore, IL-2, IL-4, IL-5, and IFN-gamma secretion by Hut 78 cells or CD3(+) T cells stimulated with PMA plus ionomycin or anti-CD3 antibody plus PMA were inhibited in a concentration-dependent manner by BTPs. Therefore, BTPs inhibit a wide spectrum of cytokine production including TH1 and TH2 type cytokines. Taken together, these compounds may be useful for treating autoimmune diseases and organ transplant rejection. |
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Keywords: | Immunomodulator IL-2 Cytokines RNA protection assay ELISA Ca2+-dependence |
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