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Stat3 Activation in Acute Lung Injury¹

Hongwei Gao^*, Ren-Feng Guo^*, Cecilia L. Speyer^*, Jayne Reuben^*, Thomas A. Neff^*, L. Marco Hoesel^*, Niels C. Riedemann^*, Shannon D. McClintock^*, J. Vidya Sarma^*, Nico Van Rooijen, Firas S. Zetoune^* and Peter A. Ward^2,*

^* Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Cell Biology and Immunology, Vrije Universiteit, Amsterdam, The Netherlands

Stat3 plays diverse roles in biological processes including cell proliferation, survival, apoptosis, and inflammation. Very little is known regarding its activation and function in the lung during acute inflammation. We now show that Stat3 activation was triggered in lungs and in alveolar macrophages after intrapulmonary deposition of IgG immune complexes in rats. Low levels of constitutive Stat3 were observed in normal rat lungs as determined by the EMSA. Stat3 activity in whole lung extracts increased 2 h after initiation of IgG immune complex deposition, reaching maximal levels by 4 h, whereas Stat3 activation was found in alveolar macrophages as early as 30 min after onset of injury. Expression and activation of Stat3 mRNA, protein, and protein phosphorylation was accompanied by increased gene expression of IL-6, IL-10, and suppressor of cytokine signaling-3 in whole lung tissues. Both Tyr⁷⁰⁵ and Ser⁷²⁷ phosphorylation were involved in Stat3 activation as assessed in whole lung extracts. C5a (complement 5, fragment a) per se can induce phosphorylation of Ser⁷²⁷ of Stat3. In vivo, Stat3 activation was dramatically suppressed by depletion of neutrophils or lung macrophages, resulting in reduced gene expression of IL-6 and IL-10 in whole lung tissues. Using blocking Abs to IL-6, IL-10, and C5a, Stat3 activation induced by IgG immune complexes was markedly diminished. These data suggest in the lung injury model used that activation of Stat3 in lungs is macrophage dependent and neutrophil dependent. IL-6, IL-10, and C5a contribute to Stat3 activation in inflamed rat lung.

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