title: NF-kappaB activation during IgG immune complex-induced lung injury: requirements for TNF-alpha and IL-1beta but not complement.
abstract: The development of acute lung inflammatory injury induced by alveolar deposition of IgG immune complexes in rats requires increased production of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) as well as the complement activation product, C5a. Transcription of TNF-alpha and IL-1beta genes are known to be regulated by the nuclear factor-kappa B (NF-kappaB). During IgG immune complex-induced lung inflammation, NF-kappaB has been shown to be activated in both alveolar macrophages and whole lung tissues. In the current studies we sought to determine whether TNF-alpha, IL-1beta, the complement system and oxidants contribute to the activation of NF-kappaB in the lung. Electrophoretic mobility shift analysis of nuclear extracts from whole lung tissues demonstrated that NF-kappaB activation induced by the presence of IgG immune complexes occurred independently of the complement system and neutrophils. Intrapulmonary instillation of TNF-alpha or IL-1beta into normal lung induced NF-kappaB, whereas C5a was incapable of causing NF-kappaB activation. In alveolar macrophages stimulated in vitro with IgG immune complexes, NF-kappaB activation was greatly attenuated in the presence of antibodies to TNF-alpha or IL-1beta. Similarly, in vivo blockade of TNF-alpha or IL-1beta suppressed lung NF-kappaB activation during IgG immune complex-induced lung injury. N-acetylcysteine, but not catalase, suppressed activation of lung NF-kappaB. These data suggest that TNF-alpha and IL-1beta function in an autocrine or paracrine manner to amplify the lung inflammatory response through activation of NF-kappaB. Oxidants not derived from neutrophils also appear to play a role in this process, whereas complement activation products are not involved in this phenomenon.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA. ablent@umich.edu
authors.forename: A B
authors.initials: AB
authors.lastname: Lentsch
authors.forename: B J
authors.initials: BJ
authors.lastname: Czermak
authors.forename: N M
authors.initials: NM
authors.lastname: Bless
authors.forename: P A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000542:Alveolitis, Extrinsic Allergic / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002374:Catalase / Q000494:pharmacology; D015936:Complement C5a / Q000494:pharmacology / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D007105:Immune Complex Diseases / Q000276:immunology / Q000378:metabolism*; D007074:Immunoglobulin G / Q000276:immunology*; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D007074:Immunoglobulin G; D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a; D002374:Catalase; D000111:Acetylcysteine