TH1 and TH2 cytokine inhibition by 3,5-bis(trifluoromethyl)pyrazoles, a novel class of immunomodulators.
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.
Chen
Yung- Wu
Y
Immunological Disease Research, AP9 R46R, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA. yung-wu.chen@abbott.com
Smith
Morey L
ML
Chiou
Grace X
GX
Ballaron
Stephen
S
Sheets
Michael P
MP
Gubbins
Earl
E
Warrior
Usha
U
Wilkins
Julie
J
Surowy
Carol
C
Nakane
Masaki
M
Carter
George W
GW
Trevillyan
James M
JM
Mollison
Karl
K
Djuric
Stevan W
SW
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002118:Calcium / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D003208:Concanavalin A / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D015759:Ionomycin / Q000276:immunology; D007476:Ionophores / Q000276:immunology; D019169:Jurkat Cells / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D011401:Promoter Regions, Genetic / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology*; D012313:RNA / Q000235:genetics / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007376:Interleukin-2; D007476:Ionophores; D011720:Pyrazoles; D003208:Concanavalin A; D015759:Ionomycin; D012313:RNA; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium