RESUMO
Fcgamma receptors (FcgammaR) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in IC-induced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3Kgamma abrogates C5aR signaling that is crucial for FcgammaR-mediated activation of lung macrophages. Thus, in PI3Kgamma(-/-) mice, IgG IC-induced FcgammaR regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3Kgamma(-/-) mice but was impaired in PI3Kdelta(-/-) mice. Consequently, class IA PI3Kdelta deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3Kgamma and PI3Kdelta coordinate the inflammatory effects of C5aR and FcgammaR and define PI3Kdelta as a novel and essential element of FcgammaR signaling in the generation of C5a in IC disease.
Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Reação de Arthus/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Receptores de IgG/metabolismo , Animais , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/imunologia , Reação de Arthus/genética , Reação de Arthus/imunologia , Classe I de Fosfatidilinositol 3-Quinases , Classe Ib de Fosfatidilinositol 3-Quinase , Modelos Animais de Doenças , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Inflamação/enzimologia , Inflamação/genética , Inflamação/imunologia , Isoenzimas/genética , Isoenzimas/imunologia , Isoenzimas/metabolismo , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/imunologia , Receptores de IgG/genética , Receptores de IgG/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
The pleural cavity of rats was used to study the effect of altering leucocyte cyclic AMP content on the release of B-glucuronidase activity during an immediate hypersensitivity reaction. The effect on intravenous colchicine was also studied. Despite an increase of 135 to 235% in leucocyte cyclic AMP content no decrease in B-glucuronidase release was observed. Similarly, colchicine had no effect on enzyme release. It was concluded that the cyclic nucleotides and leucocyte microtubules may have no significant role to play in the release of lysosomal enzymes during acute inflammation in vivo.
Assuntos
Reação de Arthus/sangue , AMP Cíclico/sangue , Leucócitos/metabolismo , Animais , Reação de Arthus/enzimologia , Bucladesina/farmacologia , Colchicina/farmacologia , GMP Cíclico/sangue , Glucuronidase/sangue , L-Lactato Desidrogenase/sangue , Leucócitos/enzimologia , Lisossomos/enzimologia , Masculino , Ratos , Teofilina/farmacologiaRESUMO
A complex of inflammatory protease with an inhibitor was found to be present in the early phase of Arthus skin lesions in guinea pig. From the extract of inflamed lesions a complex was partially purified by chromatography on DEAE-Sephadex A-50 and GE-cellulose, in that order. The inhibitor was finally dissociated rom the protease complex by treating them with cysteine followed by Sephadex G-50 chromatography. Active protease was recovered as a single peak which also contained some inhibitor activity. The isolated inhibitor was capable of inactivating inflammatory protease as well as papain. It was electrophoretically homogenous and was identified as protein or polypeptide in the serum alpha-1-globulin fraction. The significant role of the inhibitor in regulating the acute phase of inflammatory process is emphasized.