Augmentation of in vitro interleukin 10 production after in vivo administration of interleukin 18 is activated macrophage-dependent and is probably not involved in the antitumor effects of interleukin 18.
We have previously shown that interleukin (IL)-18 protects mice from intraperitoneal transplantation with syngeneic Meth A sarcoma, and in the process induces the production of large amounts of IL-10 from mitogen-stimulated treated mouse spleen cells, with a simultaneous augmentation of natural killer (NK) cell activity. Using in vivo and in vitro cell depletion methods, we now show that the cells producing IL-10 are neither NK cells nor macrophages (M phi), but that the IL-10 production is dependent on the presence of treated mouse M phi. Anti-IL-12 and anti-CD40L neutralizing antibodies could not inhibit the production of IL-10. Although IL-18-treated normal mouse enriched T cells stimulated with anti-CD3 and anti-CD28 antibodies failed to produce IL-10, the cytokine was also undetectable in culture supernatants of IL-18-treated nude mouse spleen cells, indicating that T cells were directly involved in the induced production of IL-10. Flow cytometry for intracellular IL-10 confirmed that CD8+ T cells and other, as yet unidentified spleen cell sub-sets were secreting IL-10, but only a small percentage of CD4+ cells produced IL-10. In vivo experiments using anti-IL-10 antibody indicated that IL-10 may not be directly involved in the antitumor effects of IL-18.
Micallef
M J
MJ
Fujisaki Institute, Hayashibara Biochemical Laboratories Inc., Okayama, Japan. fujih@harenet.or.jp
Tanimoto
T
T
Kohno
K
K
Ikeda
M
M
Ikegami
H
H
Kurimoto
M
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003208:Concanavalin A; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics*; D018664:Interleukin-12 / Q000276:immunology / Q000502:physiology; D020382:Interleukin-18 / Q000494:pharmacology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000628:therapy; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000906:Antibodies; D000970:Antineoplastic Agents; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D003208:Concanavalin A; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12