Inhibitors of Src-family tyrosine kinases favour Th2 differentiation.
Two potent pyrazolo-pyrimidine inhibitors of Src-family kinases were found to enhance interleukin 4 (IL-4) and reduce interferon gamma(IFN-gamma) production in cultures of splenocytes from ovalbumin-specific TCR-transgenic BALB/c mice. The effect was increased by addition of a monoclonal antibody binding to domains 3/4 of CD4, while other antibodies binding to domain 1 had the opposite effect. The inhibitors suppressed CD40 ligand (CD40L) expression on activated CD4 T cells, which may explain this Th2 differentiating effect. More generally, the effect fits within the overall framework of signal attenuation in T cells driving this form of differentiation. The inhibitors did not revert previously induced Th1 differentiation in serial cultures of the TCR-transgenic cells. Drugs with this activity are of obvious interest as probes and potential therapeutic agents in autoimmune disease.
Gimsa
U
U
Deutsches RheumaForschungsZentrum Berlin, Germany.
Mitchison
A
A
Allen
R
R
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D002454:Cell Differentiation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D000906:Antibodies; D015704:CD4 Antigens; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D011720:Pyrazoles; D011743:Pyrimidines; D016693:Receptors, Antigen, T-Cell, alpha-beta; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D019061:src-Family Kinases