title: Immobilized IgG immune complex induces secretion of tumor necrosis factor-alpha by porcine alveolar macrophages.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is an important inflammatory mediator produced by activated monocytes and macrophages. We have previously shown that porcine alveolar macrophages (PAM) mediate bystander cytotoxicity through hydrogen peroxide production following activation with immobilized IgG immune complex (IIC) (J. Immunol. 1983; 131:1438-1442). In this report, we have investigated whether IIC induces TNF-alpha secretion by PAM. Isolated PAM from Minnesota miniature swine were cultured for 18 h with and without recombinant human interferon-gamma (rhIFN-gamma). Cultured PAM were then incubated with IIC or IgG immune complex in suspension (SIC). The supernatants generated were assessed for cytotoxic activity using a TNF-alpha-sensitive WEHI-164 cell line. Anti-recombinant human TNF-alpha (rhTNF-alpha) monoclonal antibody neutralized the observed cytotoxicity of IIC-activated PAM supernatant completely, indicating that this cytotoxicity is mediated by TNF-alpha. IIC induced TNF-alpha secretion by PAM after 3 h of incubation, reaching a plateau from 6 to 12 h and decreasing thereafter. TNF-alpha release was enhanced by pretreatment of PAM with rhIFN-gamma. SIC did not induce significant levels of TNF-alpha secretion by PAM; however, SIC with cytochalasin B-pretreated PAM induced equivalent levels of TNF-alpha secretion as IIC-activated PAM. We conclude that IIC or SIC with cytochalasin B pretreatment, both of which prevent internalization of IgG immune complex-bound Fc receptor (FcR), provide a signal for PAM to generate TNF-alpha through FcR modulation. This suggests that in vivo, deposited (immobilized) IgG immune complexes-bound FcR may be a stimulus for activation of PAM to generate TNF-alpha rather than circulating (mobilized) immune complexes, which may contribute to the pathogenesis of diffuse interstitial fibrosis of the lung, especially in idiopathic pulmonary fibrosis.
authors.affiliation: Department of Microbiology and Immunology, University of Health Sciences/The Chicago Medical School, Illinois 60064.
authors.forename: J W
authors.initials: JW
authors.lastname: Kim
authors.forename: W G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Y B
authors.initials: YB
authors.lastname: Kim
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000276:immunology*; D000943:Antigens, Differentiation / Q000502:physiology*; D003571:Cytochalasin B / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D011961:Receptors, Fc / Q000502:physiology*; D017452:Receptors, IgG; D011994:Recombinant Proteins; D012995:Solubility; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000936:Antigen-Antibody Complex; D000943:Antigens, Differentiation; D011961:Receptors, Fc; D017452:Receptors, IgG; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003571:Cytochalasin B; D007371:Interferon-gamma