Adenoviral-mediated overexpression of SOCS3 enhances IgG immune complex-induced acute lung injury.

Abstract

The lung inflammatory response caused by intratracheal deposition of IgG immune complexes (IC) includes the production of IL-6, which signals through activation of STAT transcription factors. Recently, suppressor of cytokine signaling 3 (SOCS3) has been shown to be a key negative regulator of IL-6/gp130/Jak/STAT3 signal transduction. Although SOCS3 has been implicated in several inflammatory diseases, very little is known regarding its activation and its function in the lung during acute inflammation. Our previous study showed that IL-6/STAT3 activation was triggered in lungs after intrapulmonary deposition of IgG IC in rats. In the current study, we sought to determine whether SOCS3 is playing a regulatory role in the lung inflammatory response. SOCS3 induction occurred during development of inflammation in the IgG IC model of lung injury. Overexpression of SOCS3 in lung using a recombinant adenovirus encoding murine SOCS3 resulted in substantial increases in lung vascular permeability and lung myeloperoxidase, together with enhanced levels of TNF-alpha, MIP-2, and keratinocyte-activated cytokine in bronchoalveolar lavage fluids. SOCS3 overexpression in lungs led to overproduction of bronchoalveolar lavage IL-6, but not IL-10, in this inflammatory model. We further show that activation of STAT3 was inhibited by SOCS3 overexpression as well as by anti-IL-6 treatment during IgG IC-induced lung injury, as determined by EMSA. In vitro, SOCS3 overexpression abrogated IL-6-induced activation of STAT3 in lung epithelial cells. These findings suggest SOCS3 is an important regulator of lung inflammatory injury after deposition of IgG IC.

• Authors: Hongwei Gao, L Marco Hoesel, Ren-Feng Guo, Nicholas J Rancilio, J Vidya Sarma, Peter A Ward
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 177 Issue 1 Pg. 612-20 (Jul 01 2006) ISSN: 0022-1767 [Print] United States
• PMID: 16785559 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adjuvants, Immunologic
• Antigen-Antibody Complex
• Immunoglobulin G
• Interleukin-6
• NF-kappa B
• STAT3 Transcription Factor
• Socs3 protein, mouse
• Stat3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins

Topics

• Acute Disease
• Adenoviridae (genetics)
• Adjuvants, Immunologic (administration & dosage, biosynthesis, genetics)
• Animals
• Antigen-Antibody Complex (administration & dosage, metabolism)
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Cell Line
• Feedback, Physiological (genetics, immunology)
• Immunoglobulin G (administration & dosage, metabolism)
• Inflammation (genetics, immunology, metabolism)
• Interleukin-6 (antagonists & inhibitors, biosynthesis)
• Leukocyte Count
• Lung (immunology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism, physiology)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (administration & dosage, biosynthesis, genetics)