TLR Ligands and IFN-γ exhibit Antagonistic Effects on Protease HTRA1 Expression in Rheumatoid Arthritis

Jul 03, 2014     Email"> PrintText Size

Rheumatoid arthritis (RA) is a common autoimmune disease with a prevalence of about 1% worldwide. RA is characterized by chronic inflammation and high levels of destructive mediators in the synovium, which leads to cartilage and bone destruction. HTRA1 is a secreted serine protease, which acts as both molecular chaperone and proteolytic enzyme. HTRA1 directly promotes the degradation of collogen and some other proteins in cartilage, and inhibits TGF-β signaling pathway, which is important for the generation of collogen and proteoglycans. Additionally, HTRA1 also sitimulates fibroblasts to secrete matrix metalloproteinase (MMPs), which lead to bone damage. The correlationship between HTRA1 and the occurrence and development of arthritis in clinics has been recognized. However, the micro-environmental extracellular factors and intracellular upstream events that regulate HTRA1 expression in mammalian cells are unknown.

Dr. ZHAO Yong’s group recently found that toll-like receptor 4 (TLR4) ligands LPS and tenascin-C (TNC) strongly induced HTRA1 expression, whereas IFN-γ inhibited HTRA1 expression in mouse fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the antagonistic effect of LPS and IFN-γ on HTRA1 expression was evidenced in collagen-induced arthritis mouse models and in human synovial cells. Mechanistically, TLR4 ligands and IFN-γ controlled HTRA1 expression through activation of the classical NF-κB and p38MAPK-STAT1 pathway, respectively.

This study offers new insights into HTRA1 expression and may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer. 

This study was mainly carried out by Dr. HOU Yuzhu, Dr. LIN Haijiang, Dr. ZHU Linnan in the Institute of Zoology, Chinese Academy of Sciences. This is a collaboration work of Dr. ZHAO’s laboratory with the laboratory of Dr. WANG Qiang from Institute of Zoology and the laboratory of Dr. LI Zhanguo from Peking University People’s Hospital. This serial studies were recently published in the “Arthritis & Rheumatism” (Arthritis & Rheumatism. 2013,65(11): 2835-2846;) and “The Journal of Immunology” (published online). This study was supported by grants from National Basic Research Program of China and National Natural Science Foundation for General and Key Programs.