IL-1 beta is required for IL-12 to induce production of IFN-gamma by NK cells. A role for IL-1 beta in the T cell-independent mechanism of resistance against intracellular pathogens.
Mice with the severe combined immunodeficiency (SCID) possess an IFN-gamma-dependent mechanism of resistance to the intracellular pathogens Toxoplasma gondii and Listeria monocytogenes that is dependent on IL-12-induced production of IFN-gamma by NK cells. In this report we demonstrate that IL-1 beta is required for IL-12 to stimulate production of IFN-gamma by NK cells, and that IL-1 is important in IL-12-mediated resistance to T. gondii in vivo. Stimulation of SCID mouse splenocytes with tachyzoites of T. gondii resulted in production of IFN-gamma. Addition of neutralizing Ab specific for IL-1 beta to these cultures inhibited completely the production of IFN-gamma. Similar results were obtained when LPS or L. monocytogenes were used to stimulate production of IFN-gamma by SCID mouse splenocytes. Addition of a neutralizing Ab to IL-1 alpha did not affect production of IFN-gamma by SCID mouse splenocytes stimulated with T. gondii, L. monocytogenes, or LPS. Stimulation of SCID mouse splenocytes with IL-1 beta or IL-1 alpha did not result in production of IFN-gamma but enhanced remarkably the ability of T. gondii or IL-12 to stimulate production of IFN-gamma. Furthermore, production of IFN-gamma by SCID mouse splenocytes stimulated with IL-12 plus TNF-alpha was completely ablated by anti-IL-1 beta, but not by anti-IL-1 alpha. Analysis of the culture supernatants of spleen cells from SCID mice stimulated with T. gondii or IL-12 plus TNF-alpha detected low levels of IL-1 beta; addition of a neutralizing Ab to IFN-gamma resulted in a 5- to 10-fold increase in levels of IL-1 beta. Furthermore, stimulation of SCID mouse splenocytes with IL-12, in the presence of anti-IFN-gamma, resulted in an increase in detectable levels of IL-1 beta. To determine the in vivo relevance of our in vitro data, SCID mice were infected with T. gondii and treated with IL-12 alone or IL-12 in combination with an Ab specific for the type I IL-1 receptor. This Ab reduced production of IFN-gamma by SCID mouse splenocytes stimulated with either T. gondii, LPS, L. monocytogenes, or IL-12 plus IL-1 beta. In vivo administration of this Ab antagonized significantly the ability of exogenous IL-12 to delay the time to death of SCID mice infected with T. gondii.(ABSTRACT TRUNCATED AT 400 WORDS)
Hunter
C A
CA
Department of Immunology and Infectious Disease, Palo Alto Medical Foundation, CA 94301, USA.
Chizzonite
R
R
Remington
J S
JS
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D005260:Female; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000276:immunology / Q000502:physiology*; D018664:Interleukin-12 / Q000276:immunology / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008089:Listeria monocytogenes / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000628:therapy
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D008070:Lipopolysaccharides; D018664:Interleukin-12; D007371:Interferon-gamma