KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts

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Abstract

The serum level of KL-6, a MUC1 mucin, is a clinically useful marker for various interstitial lung diseases. Previous studies demonstrated that KL-6 promotes chemotaxis of human fibroblasts. However, the pathophysiological role of KL-6 remains poorly understood. Here, we further investigate the functional aspects of KL-6 in proliferation and apoptosis of lung fibroblasts. KL-6 accelerated the proliferation and inhibited the apoptosis of all human lung fibroblasts examined. An anti-KL-6 monoclonal antibody counteracted both of these effects induced by KL-6 on human lung fibroblasts. The pro-fibroproliferative and anti-apoptotic effects of KL-6 are greater than and additive to those of the maximum effective concentrations of platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor-β. These findings indicate that increased levels of KL-6 in the epithelial lining fluid may stimulate fibrotic processes in interstitial lung diseases and raise the possibility of applying an anti-KL-6 antibody to treat interstitial lung diseases.

Section snippets

Materials and methods

Materials and reagents. The reagents used in the present study were obtained as follows: Eagle’s minimum essential medium-α (MEM-α) was obtained from Nikken BioMed., Kyoto, Japan; paraformaldehyde, Triton X-100 and Hoechst 33342 were from Sigma–Aldrich, St. Louis, MO, USA; the CellTiter 96 AQueous One Solution Cell Proliferation Assay kit using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) was from Promega, Madison, WI, USA; the Cell

KL-6 accelerates proliferation of human lung fibroblasts

The presence of 100 U/ml of KL-6 in the culture medium was found to accelerate cell proliferation in all of seven human lung fibroblasts examined (Table 1). CCD-11Lu fibroblasts were selected for further experiments based on the strength of their response to KL-6. As shown in Fig. 1A, the presence of KL-6 from 1 to 1000 U/ml accelerated the proliferation of CCD-11Lu in a dose-dependent manner. Furthermore, addition of anti-KL-6 mAb inhibited the KL-6-induced proliferation of CCD-11Lu in a

Discussion

In the present study, we have demonstrated that KL-6 molecules have a pro-proliferative effect on all human lung fibroblasts that were examined in vitro. We also demonstrated that KL-6 has an anti-apoptotic effect in that it rescues lung fibroblasts from apoptosis induced by anti-Fas mAb and cycloheximide. In addition, we confirmed that addition of anti-KL-6 mAb to the cell culture blunted both the pro-proliferative and anti-apoptotic effects of KL-6 on CCD-11Lu cells in a dose-dependent

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