IL-6/sIL-6R enhances cathepsin B and L production via caveolin-1-mediated JNK-AP-1 pathway in human gingival fibroblasts
✍ Scribed by Tomoko Yamaguchi; Koji Naruishi; Hideo Arai; Fusanori Nishimura; Shogo Takashiba
- Book ID
- 102314558
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 411 KB
- Volume
- 217
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Interleukin (IL)‐6 has an important role in inflammatory diseases. Lysosomal enzymes cathepsins are widely expressed as cysteine proteases regulating inflammatory process. Caveolin‐1 (Cav‐1) is a scaffolding/regulatory membrane protein that interacts with signaling molecules. In this study, we investigated the role of Cav‐1 on (1) the productivity, and (2) the enzymatic activity of cathepsin B and L in human gingival fibroblasts (HGFs) treated with IL‐6 in the presence of soluble form of IL‐6 receptor (sIL‐6R). At first, we established the siRNA‐mediated Cav‐1 down‐regulating in vitro systems by transient transfection of Cav‐1 siRNA. The siRNA‐mediated Cav‐1 down‐regulated cells were treated with IL‐6/sIL‐6R for indicated times. Then, cell lysates were collected, and examined the IL‐6‐induced signaling pathway, cathepsin B and L production, and measurement of cathepsins activity. To investigate the cathepsin L activity, cathepsin‐(B + L) activity was measured after pretreatment with CA‐074Me, a specific inhibitor for cathepsin B. We found that IL‐6/sIL‐6R enhanced significantly both production and activity of cathepsin B and L in HGFs. Interestingly, IL‐6‐mediated phosphorylation of both p44/42 MAPK and JNK was dramatically suppressed in Cav‐1 down‐regulated HGFs treated with IL‐6/sIL‐6R. In addition, both production and activity of cathepsin B and L were also significantly suppressed. Importantly, we demonstrated that JNK inhibition, but not p44/42 MAPK inhibition, significantly diminished IL‐6/sIL‐6R‐induced cathepsin B and L production. Taken together, we concluded that IL‐6/sIL‐6R enhances cathepsin B and L production via IL‐6/sIL‐6R‐mediated Cav‐1‐JNK‐AP‐1 pathway in HGFs. Our findings indicate that Cav‐1 might be a therapeutic target for IL‐6‐mediated tissue degradation in periodontitis. J. Cell. Physiol. 217: 423–432, 2008. © 2008 Wiley‐Liss, Inc.