ROLE OF CA2+ IN PROSTAGLANDIN E(2)-INDUCED T-LYMPHOCYTE PROLIFERATIVE SUPPRESSION IN SEPSIS

Prostaglandin E(2) (PGE(2)) has been known to modulate immune responses by inhibiting T-cell activation following hemorrhagic and traumatic injury. Recently, we documented a sepsis-related depression in concanavalin A (ConA)-induced T-cell proliferation and intracellular Ca2+ (Ca-i(2+)) mobilization. The present study evaluated the potential role of PGE(2) in the sepsis-related attenuation in Ca2+ signaling and proliferation in T cells. Sepsis was induced in rats by implanting into their abdomen fecal pellets containing Escherichia coli (150 CFU) and Bacteroides fragilis (10(4) CFU). A group of rats implanted with septic pellets were treated with indomethacin at three consecutive time points, Levels of PGE(2) in blood were measured with a radioimmunoassay kit, ConA-induced [Ca2+](i) mobilization in T cells obtained from indomethacin-treated and untreated rats was measured with Fura-2 and microfluorometry. We observed a 10-fold increase in PGE(2) levels in the circulation of septic rats compared with levels in rats implanted with bacterium-free sterilized pellets. The proliferative response and Ca-i(2+) mobilization were significantly depressed in T cells obtained from septic rats 48 h after implantations compared with those in rats implanted with sterile pellets. However, treatment of rats with the cyclooxygenase inhibitor indomethacin prevented the sepsis-related depression in ConA-induced T-cell Ca2+, mobilization as well as proliferation. Further, incubation of T cells from nonimplanted control rats with PGE, resulted in a substantial depression in both T-cell proliferation and Ca-i(2+) mobilization. The restoration of T cell proliferation and Ca2+ signaling after indomethacin treatment of septic rats and the depression in the mitogen responsiveness in T cells previously exposed to PGE, suggest that the PGE(2) does play a significant role in the modulation of T-cell responses in septic rats and that such PGE(2)-induced suppression in T-cell activation is likely due to an attenuation in Ca2+ signaling.