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Anti-Chemokine Autoantibody:Chemokine Immune Complexes Activate Endothelial Cells via IgG Receptors

¹ Department of Biochemistry and ² Department of Pathology, University of Texas Health Science Center, Tyler, Texas; ³ School of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California; and ⁴ Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas

Correspondence and requests for reprints should be addressed to Anna K. Kurdowska, Ph.D., Department of Biochemistry, University of Texas Health Center, 11,937 U.S. Highway 271, Tyler, Texas 75708-3154. E-mail: anna.kurdowska{at}uthct.edu

Our previous studies revealed that the presence in lung fluids of anti–IL-8 autoantibody:IL-8 immune complexes is an important prognostic indicator for the development and outcome of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Anti–IL-8:IL-8 complexes purified from lung edema fluids trigger chemotaxis of neutrophils, induce activation of these cells, and regulate their apoptosis, all via IgG receptor, FcRIIa. Importantly, increased levels of FcRIIa are present in lungs of patients with ARDS, where FcRIIa is partially associated with anti–IL-8:IL-8 complexes. In the current study, we demonstrate the ability of anti–IL-8:IL-8 complexes to promote an inflammatory phenotype of human umbilical vein endothelial cells via interaction with FcRIIa. Human umbilical vein endothelial cells cultured in the presence of the complexes become activated, as shown by increased phosphorylation of ERK, JNK, and Akt, and augmented nuclear translocation of NF-B. Anti–IL-8:IL-8 complexes also up-regulate expression of intracellular adhesion molecule (ICAM)-1 on the cell surface. Furthermore, we detected increased levels of ICAM-1 on lung endothelial cells from mice in which lung injury was induced by generating immune complexes in alveolar spaces. On the other hand, ICAM-1 expression was unchanged in lungs of chain–deficient mice, lacking receptors that interact with immune complexes. Moreover, in lung tissues from patients with ARDS, anti–IL-8:IL-8 complexes were associated with endothelial cells that expressed higher levels of ICAM-1. Our current findings implicate that anti-chemokine autoantibody:chemokine immune complexes, such as IL-8:IL-8 complexes, may contribute to pathogenesis of lung inflammation by inducing activation of endothelial cells through engagement of IgG receptors.

Key Words: chemokine • autoantibody • lung • IgG receptor

CLINICAL RELEVANCE Our findings indicate that anti-chemokine autoantibody:chemokine immune complexes, such as anti-IL-8:IL-8 complexes, may contribute to pathogenesis of lung inflammation associated with acute lung injury/acute respiratory distress syndrome by inducing activation of endothelial cells through engagement of IgG receptors.