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A2925 - Immunoglobulin A Induces Production of Inflammatory Cytokines and Collagen I by Human Lung Fibroblasts
Author Block: S. Arakawa1, M. Suzukawa1, K. Kobayashi1, H. Matsui1, T. Nagase2, K. Ohta1; 1Center for Pulmonary Diseases, National Hospital Organization, Tokyo National Hospital, Kiyose, Japan, 2Resp. Medicine, Univ of Tokyo Hospital, Tokyo, Japan.
Immunoglobulin A (IgA) is the most abundant immunoglobulin in human. In the respiratory tract, plasma cells that reside in submucosa generate polymeric, J chain-containing IgA, which is selectively bound to polymeric immunoglobulin receptor on the basolateral surfaces of mucosal epithelial cells. Then IgA is released as secretory IgA (sIgA) into the lumen where it acts as an important first line of defense. The important role of sIgA in respiratory tract goes not only destroying the antigens at site but preventing invasion of foreign substances into the circulatory system. On the contrary to IgA’s protective effect on pathogenesis of asthma and infectious respiratory diseases, it is reported that IgA can be used as a prognostic marker for idiopathic pulmonary fibrosis (IPF). IPF patients with high serum IgA are reported to show worse survival. Therefore, in this study, we sought to elucidate the direct effect of sIgA on lung fibroblasts, a major player in the pathogenesis of IPF. Normal human lung fibroblasts (NHLFs) were cultured with sIgA, and cytokine production was measured using Cytometric Bead Assay and real-time PCR. We assessed production of collagen (Col) I and α smooth muscle actin (αSMA) using Western Blotting and PCR. We checked expression levels of known IgA receptors on NHLFs by flowcytometry. To evaluate cell function alteration, we performed a gel contraction assay. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post-hoc test or t-test for pair-wise comparisons. As a result, both the protein levels in the culture supernatant and the mRNA levels of inflammatory cytokines, i.e., IL-6, IL-8 and CCL2, were significantly and dose-dependently elevated with sIgA stimuli. Western Blotting revealed upregulation of Col I and αSMA production by sIgA. Interestingly, sIgA significantly promoted gel contraction. Among the known receptors, we found a robust expression of CD71 (transferrin receptor) on NHLFs. Its knockdown with siRNA suppressed cytokine production at least partially by sIgA-treated NHLFs. In conclusion, an important role of sIgA in the pathogenesis of lung fibrosing diseases including IPF may be to promote lung inflammation and fibrosis by enhancing production of inflammatory cytokines, Col I and αSMA by lung fibroblasts, which may be caused at least partly by binding to CD71.