INDUCTION OF HEAT SHOCK PROTEIN BY INTERLEUKIN 1 INTRAAMNIOTIC INFUSION

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Induction of proinflammatory cytokine synthesis leading to prostaglandin production and myometrial contractions is an established pathway of infection-related preterm labor. The mechanisms limiting cytokine-induced preterm contractions have only recently been investigated. Interleukin-1 (IL-1) receptor antagonist has been identified in amniotic fluid (AF) and shown to increase in concentration following cytokine activation. We now report that infusion of IL-1 into the AF also induces synthesis of heat shock protein (HSP). Induction of HSP gene transcription has been shown to inhibit transcription of the IL-1 and tumor necrosis factor (TNF) genes. Chronically instrumented rhesus macaques with timed gestations were infused with recombinant human IL-1b. At timed intervals AF was obtained and IL-1, TNF, and IL-6 concentrations were determined. Levels of the 60kD HSP were determined by EIA using monoclonal antibodies to human HSP. Amniotic fluid was also tested for the presence of 60kD and 70kD HSP by Western blots. Prior to infusion, TNF, IL-6, and HSP were undetectable in AF. Following IL-1 infusion, AF TNF and IL-6 levels quickly rose. A 60kD HSP appeared in AF coincident with decreasing intraamniotic concentrations of TNF and IL-6. In 4 monkeys, peak AF HSP concentrations of 1-5 ng/ml were estimated using a standard curve generated with human HSP. Western blot analysis confirmed the absence of HSP in AF prior to IL-1 infusion and the appearance of 60kD and 70kD HSP in AF following infusion. Thus, induction of HSP synthesis in the amniotic cavity by proinflammatory cytokines may be another regulatory mechanism to limit cytokine synthesis and the subsequent cascade leading to preterm contractions.