Cathepsin B Regulates Collagen Expression by Fibroblasts via Prolonging TLR2/NF-κB Activation

Abstract

Fibroblasts are essential for tissue repair due to producing collagens, and lysosomal proteinase cathepsin B (CatB) is involved in promoting chronic inflammation. We herein report that CatB regulates the expression of collagens III and IV by fibroblasts in response to a TLR2 agonist, lipopolysaccharide from Porphyromonas gingivalis (P.g. LPS). In cultured human BJ fibroblasts, mRNA expression of CatB was significantly increased, while that of collagens III and IV was significantly decreased at 24 h after challenge with P.g. LPS (1 μg/mL). The P.g. LPS-decreased collagen expression was completely inhibited by CA-074Me, the specific inhibitor of CatB. Surprisingly, expression of collagens III and IV was significantly increased in the primary fibroblasts from CatB-deficient mice after challenge with P.g. LPS. The increase of CatB was accompanied with an increase of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and a decrease of IκBα. Furthermore, the P.g. LPS-increased 8-OHdG and decreased IκBα were restored by CA-074Me. Moreover, 87% of CatB and 86% of 8-OHdG were colocalized with gingival fibroblasts of chronic periodontitis patients. The findings indicate the critical role of CatB in regulating the expression of collagens III and IV by fibroblasts via prolonging TLR2/NF-κB activation and oxidative stress. CatB-specific inhibitors may therefore improve chronic inflammation-delayed tissue repair.

Determination of the concentration of cathepsin B bySPRI biosensor in children with appendicitis, and its correlation with proteasomes

“…Cathepsin B regulates collagen expression by fibroblasts via prolonging toll-like receptor 2 (TLR2)/NF-κB activation during chronic inflammation and oxidative stress. 4 It is involved in degrading the intracellular and extracellular collagen produced by fibroblasts, thereby influencing the mechanisms of delayed tissue repair during chronic inflammation. Collagen type III and type IV in fibroblasts are important in wound healing and tissue remodeling.…”

“…1 Cathepsin B is also responsible for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation through autophagy degradation of inhibitor of κBα (IκBα) in microglia and macrophages. 4 The inhibition of CatB can rescue cells from tumor necrosis factor (TNF)-induced apoptosis. 5 The inhibition of cathepsins leads to significant neuroprotection, because treatment with a specific CatB inhibitor significantly reduces infarct volumes.…”

“…1 Elevated levels of CatB in fibroblasts are typically observed in many chronic inflammatory diseases, including rheumatoid arthritis as well as periodontitis, because CatB promotes inflammation involved in the production of mature interleukin 1β (IL-1β). 4,[6][7][8] Interleukin 1β is a potent pro-inflammatory cytokine that is crucial for host-defense responses to infection and injury. 9 Lysosomal membrane rupture and CatB activity are important for the activation of the NLRP3 inflammasome in response to some stimuli, where the inhibition of CatB attenuates IL-1β release.…”

“…10,11 Cathepsin B also degrades collagens in fibroblasts and leads to tissue destruction. 4,12 Proteasome is generally considered a dominating component in protein degradation pathway. 13 Through degrading regulatory proteins or their inhibitors, proteasome regulates many cellular transduction pathways.…”

Screening for signatures of selection of Tianzhu white yak using genome‐wide re‐sequencing

“…; Li et al . ). Consequently, the above‐mentioned genes can be viewed as new candidate genes for molecular regulatory factors affecting coat color in yaks.…”