Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids.
Progesterone may contribute to the maternal suppression of immunity to the fetus by modulating the Th1/Th2 balance. To clarify whether progesterone directly or indirectly affects T cell differentiation, we used two experimental systems with isolated T cells in vitro. In one system, isolated CD4+CD8+thymocytes differentiated into Th1 and Th2 by two pulse stimulations with defined combinations of ionomycin and PMA followed by the treatment with IL-12, IL-4, and IL-2. In the second system, functional differentiation was induced in purified naive CD4 T cells with cytokines and Abs to CD3 and CD28. In both systems, progesterone added with cytokines suppressed Th1 development at concentrations associated with pregnancy, but enhanced the development of IL-10-producing Th2 cells. Because IL-10 is known to inhibit APC production of IL-12, Th1 development may be also suppressed indirectly by progesterone. However, progesterone failed to enhance IL-10 production in the absence of IL-12. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 inhibited Th1 development and enhanced Th2 development, as did progesterone, indicating that p38 MAPK and extracellular signal-regulated kinase pathways are involved in Th1 development. However, the progesterone effects may not be simply due to a modulation of MAPK activities, because the inhibitor did not significantly affect the development of IL-10-producing cells in the presence or absence of progesterone. Glucocorticoids exerted effects similar to those of progesterone on Th1/Th2 development even at lower concentrations. These results suggest that progesterone as well as glucocorticoids directly inhibit Th1 development and enhance Th2 development.
Miyaura
Hideki
H
Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194-8511, Japan.
Iwata
Makoto
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology*; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects*; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D016753:Interleukin-10; D015847:Interleukin-4; D011374:Progesterone; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003345:Corticosterone