NEITHER INTERLEUKIN-6 NOR SIGNALING VIA TUMOR-NECROSIS-FACTOR RECEPTOR-1 CONTRIBUTE TO THE ADJUVANT ACTIVITY OF ALUM AND FREUNDS-ADJUVANT

The potential contribution made by the inflammatory cytokines, interle ukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) to the adju vant activity of aluminium hydroxide gels (Alum) or Freund's complete adjuvant (FCA) was studied by comparing the immunological responses of IL-6- or TNF receptor 1- (p55; TNFR-1) deficient mice with immunocomp etent control mice. While both TNFR-1- and IL-6-deficient mice primed with ovalbumin (OVA) prepared in either Alum or FCA produced similar I gG1 responses in comparison to control mice, the pattern of T-helper t ype 1-(Th1) dependent IgG2a production was significantly altered. In T NFR-1-deficient mice, TgG2a responses were greater than in control mic e when FCA, but not when Alum, was used as an adjuvant. Correspondingl y, spleen cells from FCA-inoculated TNFR-1-deficient mice restimulated with antigen in vitro produced higher Th1 cytokine (interferon-gamma; IFN-gamma) levels with no alteration in Th2 cytokine (IL-4, IL-5, IL- 6 and IL-10) production in comparison with wild-type mice. Higher leve ls of IgG2a were also detected in IL-6-deficient mice compared with wi ld-type mice following inoculation with OVA prepared in either FCA or in Alum, Furthermore, analysis of cytokine production by spleen cells revealed that both Th1 and Th2 cytokine production was higher in IL-6- deficient mice compared with control mice. As the majority of the effe cts of TNF-alpha are mediated via TNFR-1, we conclude that this cytoki ne inhibits the adjuvant activities of FCA. Furthermore, the results a lso imply that immunopotentiating effects of FCA or Alum adjuvant are both inhibited by IL-6.