Lipopolysaccharide directly stimulates the intrapituitary interleukin-6 production by folliculostellate cells via specific receptors and the p38 alpha mitogen-activated protein kinase/nuclear factor-kappa B pathway

Bacterial lipopolysaccharide (LPS) activates the immune system and induces increases in peripheral cytokines, which, in turn, affect the endocrine sys tem. In particular, LPS-induced cytokines stimulate the hypothalamic-pituit ary-adrenal axis to increase levels of antiinflammatory-acting glucocortico ids. In the present work, we show that LPS directly stimulates interleukin (IL)-6 release by mouse pituitary folliculostellate (FS) TtT/GF tumor cells and FS cells of mouse pituitary cell cultures. The stimulatory effect of L PS was strongly enhanced in the presence of serum, suggesting that LPS is o nly fully active as a complex with LPS-binding protein (LBP). Both TtT/GF c ells and mouse pituitaries expressed CD14, which binds the LPS/LBP complex, and Toll-like receptor type 4, which induces LPS signals. LPS increased ph ospoinositol turnover in TtT/GF cells and induced phosphorylation of p38 al pha mitogen-activated protein kinase and the inhibitor (I kappaB) of nuclea r factor-kappa B. Nuclear factor-kappa B was activated by LPS in TtT/GF cel ls. Functional studies demonstrated that My4 (an antibody blocking the inte raction between LPS/LBP and CD14), SB203580, (a specific inhibitor of p38 a lpha mitogen-activated protein kinase phosphorylation), dexamethasone, and the messenger RNA translation inhibitor cycloheximide all inhibited LPS-ind uced IL-6 production by TtT/GF cells and mouse pituitary FS cells. LPS-indu ced intrapituitary IL-6 may modulate the function of anterior pituitary cel ls during bacterial infection/inflammation.