title: Regulatory effects of endogenous interleukin-1 receptor antagonist protein in immunoglobulin G immune complex-induced lung injury.
abstract: IL-1 receptor antagonist (IL-1Ra) has regulatory effects on IL-1 activity both in vitro and in vivo. In the IgG immune complex model of lung injury in rats, exogenously administered human IL-1Ra suppressed neutrophil recruitment and ensuing lung injury. In this study, we sought to determine if endogenous rat IL-1Ra might regulate this lung-inflammatory response. By Northern blot analysis of lung mRNA and Western analysis of bronchoalveolar lavage (BAL) fluids, rat IL-1Ra expression was found to increase during development of inflammation in IgG immune complex-mediated alveolitis. By immunostaining, alveolar macrophages and recruited neutrophils were the apparent sources of IL-1Ra. In vivo blocking of endogenous IL-1Ra resulted in a 53% increase in lung vascular permeability and a 180% increase in BAL fluid neutrophils. In companion studies, a significant increase in IL-1beta was found, whereas no significant change in TNF-alpha activity was observed. Whereas the in vivo regulatory effects of IL-1R appear to be limited to IL-1beta, IL-10 regulates both IL-1beta and TNF-alpha in this model, reflected by a 48% increase in BAL IL-1beta in rats treated with anti-IL-10. These findings suggest that IL-1Ra is an intrinsic regulator of inflammatory injury after deposition of IgG immune complexes and that it regulates production of IL-1beta.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Shanley
authors.forename: J L
authors.initials: JL
authors.lastname: Peters
authors.forename: M L
authors.initials: ML
authors.lastname: Jones
authors.forename: S W
authors.initials: SW
authors.lastname: Chensue
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: P A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000542:Alveolitis, Extrinsic Allergic / Q000503:physiopathology*; D000818:Animals; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D007105:Immune Complex Diseases / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012795:Sialoglycoproteins / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017931:DNA Primers; C507763:IL1RN protein, human; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha