Abstract
LL-37 is the only human cathelicidin-family host defense peptide and has been reported to interact with invading pathogens causing inflammation at various body sites. Recent studies showed high levels of LL-37 in the synovial-lining membrane of patients with rheumatoid arthritis, a common type of inflammatory arthritis. The present study aims to investigate the role of LL-37 on mechanisms associated with pathogenesis of inflammatory arthritis. The effects of LL-37 on the expression of proinflammatory cytokines, hyaluronan (HA) metabolism-related genes, cell death-related pathways, and cell invasion were investigated in SW982, a human synovial sarcoma cell line. Time-course measurements of proinflammatory cytokines and mediators showed that LL-37 significantly induced IL6 and IL17A mRNA levels at early time points (3–6 hr). HA-metabolism-related genes (i.e., HA synthase 2 (HAS2), HAS3, hyaluronidase 1 (HYAL1), HYAL2, and CD44) were co-expressed in parallel. In combination, LL-37 and IL17A significantly enhanced PTGS2, TNF, and HAS3 gene expression concomitantly with the elevation of their respective products, PGE2, TNF, and HA. Cell invasion rates and FN1 gene expression were also significantly enhanced. However, LL-37 alone or combined with IL17A did not affect cell mortality or cell cycle. Treatment of SW982 cells with both LL-37 and IL17A significantly enhanced IKK and p65 phosphorylation. These findings suggest that the chronic production of a high level of LL-37 may synchronize with its downstream proinflammatory cytokines, especially IL17A, contributing to the co-operative enhancement of pathogenesis mechanisms of inflammatory arthritis, such as high production of proinflammatory cytokines and mediators together with the activation of HA-metabolism-associated genes and cell invasion.
Highlights
Inflammatory arthritis is a group of diseases characterized by inflammation of the joints or surrounding tissues
The present study aimed to investigate the effects of LL-37 alone and in combination with interleukin 17A (IL17A), on the mechanisms related to inflammatory arthritis pathogenesis in the human synovial sarcoma cell line, SW982
LL-37 alone and in combination with IL-17 enhances mechanisms related to inflammatory arthritis and HA-metabolism-associated genes were examined, as well as cell death pathways and cell invasion
Summary
Inflammatory arthritis is a group of diseases characterized by inflammation of the joints or surrounding tissues. Rheumatoid arthritis (RA) is one of the most common inflammatory arthritis diseases. It is an autoimmune disease characterized by the chronic inflammation of the synovial membrane. Potential causes of inflammatory arthritis and RA are thought to involve both genetic and environmental factors [2, 3], and its pathogenesis involves the high production of proinflammatory cytokines, such as tumor narcosis factor (TNF), interleukin 1 beta (IL1B), interleukin 6 (IL6), and interleukin 17A (IL17A), inducing autoimmune activity, thereby inflaming the synovial membrane [4]. Inflamed synoviocytes divide uncontrollably, due to the impairment of programed cell death pathways, including apoptosis, necroptosis, and autophagy [5]
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