IL-1 RECEPTOR ANTAGONIST (IL-1RA) EXPRESSION, FUNCTION, AND CYTOKINE-MEDIATED REGULATION DURING MYCOBACTERIAL AND SCHISTOSOMAL ANTIGEN-ELICITED GRANULOMA-FORMATION

Granulomas (GR) mediated predominantly by Th1/type 1 (IFN-gamma) and T h2/type 2 (IL-4, IL-5, IL-10) cytokines were induced by i.v. injection of sensitized CBA/J mice with carbohydrate beads coated with Mycobact erium tuberculosis or Schistosoma mansoni egg Ags, respectively. GR ma crophages (M phi) from types 1 and 2 GR both produced IL-1ra, but the former showed accelerated IL-1ra-producing capacity, releasing two- to threefold greater amounts on day 4 than those of type 2 GR, as measur ed by sandwich ELISA. In vivo depletion of IL-1ra exacerbated GR size and augmented regional cytokine production in both types of responses. To determine the critical cytokines mediating IL-1ra expression, oil- elicited peritoneal M phi were exposed to graded doses (0.1 to 10 ng/m l) of cytokines (IL-1 beta, IL-2, IL-4, IL-10, IL-12, lFN-gamma, and T NF-alpha) for 24 h, then stimulated with opsonized zymosan. Of the cyt okines tested, lFN-gamma and TNF-alpha were the best costimuli for IL- 1ra production in the presence of zymosan, whereas IL-1 beta, IL-10, a nd IL-12 were not active. In vivo depletion of IL-4, IL-10, IL-12, IFN -gamma, or TNF-alpha with 5 mg of cytokine-specific neutralizing rabbi t IgG revealed that IFN-gamma and TNF-alpha were required for maximal IL-1ra production by M phi. Furthermore, the delayed IL-1ra production by type 2 GR M phi could be related to later TNF-alpha production. Ou r findings indicate that IL-1ra is a common regulatory product of infl ammatory M phi and is particularly promoted by type 1 cytokines, lFN-g amma, and TNF-alpha.