Progesterone Participates In Toll-like Receptor Signaling In Macrophages

Progesterone has been not only recognized as essential for the establishment and maintenance of pregnancy,but also involved in the immune regulation,affecting the severity of some autoimmune diseases.Mainly at concentrations commensurate with pregnancy,progesterone can affect the immune response of rodent and human through its receptor to play a role as a transcription factor,primarily through the progesterone intracellular receptors in immune regulation.Progesterone can spread into the membrane easily.It will combine with specific receptor once into the cell,then it transfer into the nucleus as a transcription factor regulating the expression of certain genes,such as binding to the NF-κB and AP-1,reducing the expression of pro-inflammatory cytokines,such as TNF-a and IL-1β,or increasing the expression of Th2 cytokines such as IL-4 and IL-10.Progesterone in physiological concentrations can also inhibit the production of pro-inflammatory cytokines induced by LPS,such as TNFa and IL-1b.However,the specific mechanism of how progesterone regulates the immune response remains unclear.Toll-like receptors(TLRs),which are broadly expressed on immune cells such as macrophages and dendritic cells,are important pattern-recognition receptors(PRRs) in innate immune response.TLRs are evolutionarily conserved to recognize pathogen associate molecular patterns(PAMPs).Upon recognition of PAMPs,TLRs activate downstream signal molecules such as MAPK and NF-κB and regulate the production of proinflammatory cytokines and co-stimulators in immune cells,and consequently initiate innate immunity and enhance adaptive immunity. The suppressor of cytokine signaling(SOCS) family is known as a class of negative regulation factors produced by the cells and the feedback of blocking cytokine signal transduction process.SOCS1 can inhibit the transduction of IL-2,IL-3,IL-6,LIF and other cytokines.SOCS1 was also identified as inhibitory regulator of the Janus kinase(JAK)-signal transducer and transcription(STAT) pathway of cytokine receptor signaling.SOCS1 can inhibit the kinase activity through high-affinity combination of its SH2 domain with the tyrosine residues in the JH1 region of the JAK(JAK1-3,TYK2) catalytic domain.The expression of SOS1 may been induced by a variety of cytokines, growth factors,endogenous immune stimulus such as LPS.Furthermore,SOCS1 can block TLR signal transduction activated by TLR ligands such as LPS in the macrophages.SOCS1 can also regulate the activation of the immune response in vivo. In this study,we demonstrated that progesterone could suppress LPS and CpG ODN induced TLRs signaling pathway.Progesterone pretreatment can significantly inhibit TLR4 and TLR9-mediated IL-6 and NO expression in the macrophages.Furthermore, we found that progesterone can inhibit the expression of LPS-induced nitric oxide synthase,down-regulate TLR4 expression and nuclear factor-κB(NF-κB) activity. Consistently,as a negative feedback inhibitor,the expression of suppressor of cytokine signaling(SOCS1) protein was up-regulated by progesterone in LPS-stimulated macrophages.These results support the concept that progesterone might inhibit innate immune response by suppressing NF-κB activation and enhancement of SOCS1 expression,providing a possible mechanistic explanation for the function of progesterone in regulating innate immune responses.