SOLUBLE RECEPTORS NEUTRALIZING TNF-ALPHA AND IL-1 BLOCK STRESS-TRIGGERED MURINE ABORTION

PROBLEM: In several models of abortion in rodents, the success or fail ure of the implanted embryos is determined by a balance between pro-in flammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-2, interleukin-l (IL-1), and gamma-interferon, and cytokin es that counteract the former, such as interleukin-10 and transforming growth factor-beta 2 (TGF-beta 2)-related suppressor factor. Stress c an trigger abortions in susceptible strains of mice and is thought to reflect the pathogenesis of some types of miscarriage in human pregnan cy. In mice, stress increases levels of the abortogenic cytokine TNF-a lpha and decreases the suppressive activity of TGF-beta 2-related fact or via a neurotransmitter substance P (SP)-dependent pathway. Evidence for a role of pro-inflammatory cytokines in SP-mediated abortions in vivo is indirect. METHODS: Direct evidence for a role of IL-1 and TNF- alpha in stress-triggered abortions was sought by injecting pregnant f emale mice with soluble receptors neutralizing TNF-alpha (rhuTNFR:Fc) or IL-1 (rmIL-1R) beginning 1 day after implantation and prior to stre ss. RESULTS: The stress-triggered abortion rate was reduced by 68% whe n either TNF-alpha or IL-1 antagonists were injected. The stress-trigg ered decreased TGF-beta 2-like suppressive activity in the maternal ut erine decidua was not restored by injection of either antagonist; inde ed the soluble IL-I receptor significantly reduced suppressive activit y in unstressed control mice, and soluble TNF-alpha receptor had a les ser effect. CONCLUSIONS: Both IL-1 and TNF-alpha play a role in the pa thogenesis of stress-triggered abortions, and may induce a compensator y physiological increase in suppressive activity in normal pregnancy c ounteracting pro-inflammatory cytokines.