title: Interleukin-10 inhibits interleukin-2-induced tumor necrosis factor production but does not reduce toxicity in C3H/HeN mice.
abstract: Immunotherapy with interleukin-2 (IL-2) is limited by severe side effects thought to be mediated by the activation of immune effector cells and the induction of secondary cytokines including tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In C3H/HeN mice the primary IL-2 toxicity is the production of pleural effusion with subsequent respiratory compromise. IL-10 is a cytokine that has been shown to inhibit the generation of secondary cytokines in vitro and in vivo. In this study, in C3H/HeN mice, we tested the ability of IL-10 to inhibit IL-2-induced mononuclear cell and alveolar macrophage activation and IL-2-induced increases in serum TNF-alpha and IFN-gamma, all of which may contribute to the generation of toxicity. IL-10 was ineffective at reducing IL-2-induced pleural effusion. However, IL-10 did inhibit IL-2-induced increases in serum TNF-alpha, which was accompanied by a decrease in Golgi apparatus and rough endoplasmic reticulum in alveolar macrophages. In addition, IL-10 combined with IL-2 increased mononuclear cell activation, which may limit the ability of IL-10 to inhibit IL-2-induced IFN-gamma production and pulmonary injury.
authors.affiliation: Department of Physiology, University of Louisville, Kentucky 40292, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Lentsch
authors.forename: M J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: D E
authors.initials: DE
authors.lastname: Sims
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: S R
authors.initials: SR
authors.lastname: Wellhausen
authors.forename: F N
authors.initials: FN
authors.lastname: Miller
mesh_terms: D000818:Animals; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D006056:Golgi Apparatus / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood; D016753:Interleukin-10 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D008809:Mice, Inbred C3H; D008854:Microscopy, Electron; D010996:Pleural Effusion / Q000139:chemically induced / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma