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Mechanism of Epithelial Injury Triggered by Anti–IL-8 Autoantibody:IL-8 Immune Complexes

¹ Department of Biochemistry, University of Texas Health Center, Tyler, Texas

Correspondence and requests for reprints should be addressed to Anna K. Kurdowska, Ph.D., Department of Biochemistry, University of Texas Health Center, 11937 US Hwy 271, Tyler, TX 75708. E-mail: anna.kurdowska{at}uthct.edu

Previous studies from our laboratory revealed that the presence of anti–IL-8 autoantibody:IL-8 immune complexes in lung fluids from patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an important prognostic indicator for the development and outcome of ALI/ARDS, and that purified complexes trigger chemotaxis of human blood neutrophils, induce neutrophil activation, and modulate survival of these cells. Further, activity of the complexes is mediated by IgG receptors, FcRIIa. Significantly, anti–IL-8 autoantibody:IL-8 immune complexes are deposited in lungs of patients with ARDS via FcRIIa. Since there is persistent accumulation of these complexes in patients with ARDS, especially the ones with unfavorable prognosis, and epithelial cells express FcRIIa, we tested the hypothesis that anti–IL-8 autoantibody:IL-8 immune complexes may contribute to epithelial injury observed in patients with ALI/ARDS. Lung epithelial cells incubated with the complexes display pro-inflammatory/pro-apoptotic phenotype. We detected activation of Syk, Smad, and Egr1 in cells stimulated with anti–IL-8:IL-8 complexes, but not in control cells. Blocking of FcRIIa inhibited stimulatory activity of the complexes, indicating that FcRIIa signaling cascade regulates certain essential functions of lung epithelial cells. Moreover, anti–IL-8:IL-8 complexes have the capability to induce apoptosis of lung epithelial cells. Accordingly, spontaneous apoptosis as well as phosphorylation of pro-apoptotic proteins, Erk and Bax, was substantially increased in cells treated with the complexes, whereas the level of anti-apoptotic protein, Bcl-X_L, was diminished in these cells. Finally, anti–IL-8 autoantibody:IL-8 immune complexes stimulated lung epithelial cells to release pro-inflammatory cytokines (i.e., IL-6 and IL-8). Our data suggest that the complexes may promote epithelial cell dysfunction and loss of epithelial integrity. Importantly, high levels of anti–IL-8:IL-8 complexes detected in patients who do not survive ARDS may adversely impact repair of epithelial barrier.

FOOTNOTES

This work was supported by the NIH grant R01 HL073245 (A.K. Kurdowska).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 27, 2007; accepted in final form October 16, 2007)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Stankowska, D. L. Articles by Kurdowska, A. K. PubMed Articles by Stankowska, D. L. Articles by Kurdowska, A. K.