Induction of pro-inflammatory genes by serum amyloid A1 in human amnion fibroblasts

Serum amyloid A1 (SAA1) is an acute response protein, which is mainly produced by the liver, during infection. However, it remains unknown whether SAA1 can be produced in human fetal membranes where it is able to elicit events pertinent to labor initiation. We demonstrated that SAA1 was expressed in the fibroblasts and epithelium of the amnion and the trophoblasts of the chorion. Further study in human amnion fibroblasts showed that SAA1 production was augmented by interleukin-1β (IL-1β) and cortisol alone and synergistically, and SAA1 in turn induced the expression of IL-1β, interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and PGE2 production. These effects of SAA1 were mediated through activation of the NF-κB, p38 and ERK1/2 pathways via the toll-like receptor 4 (TLR4). Inhibition of TLR4 attenuated not only SAA1-induced activation of NF-κB, p38 and ERK1/2 but also increases in IL-1β, IL-6 and COX-2 expression. Moreover, SAA1 expression was increased in human amnion tissue following spontaneous labor. In conclusion, this study has demonstrated for the first time that SAA1 can be produced in human fetal membranes, which can be greatly induced in the presence of proinflammatory cytokines and glucocorticoids thereby producing effects associated with parturition.