IL-1 receptor antagonist (IL-1ra) expression, function, and cytokine-mediated regulation during mycobacterial and schistosomal antigen-elicited granuloma formation
Ruth, J.H.; Bienkowski, M.; Warmington, K.S.; Lincoln, P.M.; Kunkel, S.L.; Chensue, S.W.
Journal of Immunology 156(7): 2503-2509
1996
ISSN/ISBN: 0022-1767 PMID: 8786311 Document Number: 467893
Granulomas (GR) mediated predominantly by Th1/type 1 (interferon (IFN)- gamma ) and Th2/type 2 (interleukin (IL)-4, IL-5, IL-10) cytokines were induced by i.v. injection of sensitized CBA/J mice with carbohydrate beads coated with Mycobacterium tuberculosis or Schistosoma mansoni egg antigens, respectively. GR macrophages (M phi ) from types 1 and 2 GR both produced IL-1ra, but the former showed accelerated IL-1ra-producing capacity, releasing 2- to 3-fold greater amounts on day 4 than those of type 2 GR, as measured 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/ml) of cytokines (IL-1 beta , IL-2, IL-4, IL-10, IL-12, IFN- gamma and tumour necrosis factor (TNF)- alpha ) for 24 h and then stimulated with opsonized zymosan. Of the cytokines tested, IFN- gamma and TNF- alpha were the best co-stimuli for IL-1ra production in the presence of zymosan, whereas IL-1 beta , IL-10 and 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 rabbit IgG revealed that IFN- gamma and TNF- alpha were required for maximal IL-1ra production by M phi . The delayed IL-1ra production by type 2 GR M phi was related to later TNF- alpha production. The results indicate that IL-1ra is a common regulatory product of inflammatory M phi and is particularly promoted by type 1 cytokines, IFN- gamma and TNF- alpha .