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 Th2/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 Mycobacterium tuberculosis or Schistosoma mansoni egg Ags, respectively. GR macrophages (Mphi) 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 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-Ira expression, oil-elicited peritoneal Mphi were exposed to graded doses (0.1 to 10 ng/ml) of cytokines (IL-1beta, IL-2, IL-4, IL-10, IL-12, IFN-gamma, and TNF-alpha) for 24 h, then stimulated with opsonized zymosan. Of the cytokines tested, IFN-gamma and TNF-alpha were the best costimuli for IL-1ra production in the presence of zymosan, whereas IL-1beta, 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 Mphi. Furthermore, the delayed IL-1ra production by type 2 GR Mphi could be related to later TNF-alpha production. Our findings indicate that IL-1ra is a common regulatory product of inflammatory Mphi and is particularly promoted by type 1 cytokines, IFN-gamma, and TNF-alpha.
Ruth
J H
JH
Department of Pathology and Labortory Medicine, Veterans Affairs Medical Center, Ann Arbor, MI 48105, USA.
Bienkowski
M
M
Warmington
K S
KS
Lincoln
P M
PM
Kunkel
S L
SL
Chensue
S W
SW
D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D000947:Antigens, Helminth / Q000008:administration & dosage; D016207:Cytokines / Q000494:pharmacology* / Q000502:physiology; D005260:Female; D006099:Granuloma / Q000209:etiology / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D008198:Lymph Nodes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D011817:Rabbits; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D012550:Schistosoma mansoni / Q000276:immunology* / Q000472:pathogenicity; D012795:Sialoglycoproteins / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000942:Antigens, Bacterial; D000947:Antigens, Helminth; D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma