Effect of pro‐inflammatory and immunoregulatory cytokines on human tenocytes

Abstract

Tendon injury induces a local inflammatory response, characterized by the induction of pro-inflammatory cytokines. The aim of the present study was to analyze the effects of TNFa, IL-6 and IL-10 on key parameters of tendon homeostasis. Cultured primary human tenocytes were treated with the recombinant cytokines IL-6, IL-10, TNFa, or combinations of TNFa with IL-6 and IL-10 (10 ng/mL, 6, 24 h). Expression of type I collagen, elastin, MMP-1, TNFa, IL-1b, IL-6, IL-10, and suppressors of cytokine signaling (SOCS1, 3) was analyzed with the use of RTD-PCR, immunocytochemistry, and Western blot analysis. In response to TNFa, tenocytes reduced their type I collagen deposition but increased their elastin gene expression and highly upregulated their expression for MMP-1, pro-inflammatory (TNFa, IL-1b) and immunoregulatory (IL-6, IL-10) cytokines. TNFa stimulation augmented SOCS1, whereas SOCS3 expression in tenocytes was also induced by IL-6. The treatment of tenocytes with IL-6 and IL-10 had no effect on cytokine expression. Neither IL-6 nor IL-10 modulated the observed effects of TNFa significantly. These results indicate that TNFa strongly activates the tenocytes to amplify their own TNFa expression and, subsequently, that of other regulatory cytokines and matrix degrading enzymes. However, the impact of IL-6 and IL-10 on tenocytes remains unclear. ß

Platelet-rich Plasma Modulates the Secretion of Inflammatory/Angiogenic Proteins by Inflamed Tenocytes

“…Remarkably, our data showed that PRP had potential to downregulate COL1A1, VEGF, COX-2, IL-6, and IL-6R. Other studies have shown that tumor necrosis factor-a-activated tenocytes express high levels of MMP-1, IL-1ß, and IL-6 [17]. Actually, the cell-extrinsic response to stressors can involve both functional gene categories; first gene products likely involved in inflammation and tissue level adaptations such as angiogenesis and second genes that regulate the extracellular matrix compartment, ie, fibrillar collagens and remodeling enzymes (ie, MMP-1, MMP-3, ADAMTS4, and ADAMTS5) [18].…”

Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling

“…Proinflammatory cytokines, including TNF-a, IL-1b, IL-6, and IL-8, released upon injuries reduce the collagen production and induce vasodilation, angiogenesis, and matrix metalloproteinase (MMPs) expression in tendon repair (22)(23)(24). Chronic tendon injuries also involve inflammatory responses (22)(23)(24) closely associated with elevated MMP activities (25,26). The persistent inflammation and the disrupted balance between MMPs and tissue inhibitor of metalloproteinases (TIMPs) contribute to scarlike tendon healing and chronic matrix degradation (25,26).…”

“…A blockage of TNF-a (28) and an inhibition of MMPs (29) improved tendon healing in vivo. To better understand how inflammation and MMP activities are regulated in tendon, a series of in vitro studies investigated molecular responses in tenocytes when stimulated by proinflammatory cytokines or M1 macrophages (Mfs) (23,30). TNF-a treatment up-regulated expression of MMP-1, proinflammatory (e.g., TNF-a and IL-1b), and anti-inflammatory (e.g., IL-6 and IL-10) cytokines in human tenocytes (23).…”

“…To better understand how inflammation and MMP activities are regulated in tendon, a series of in vitro studies investigated molecular responses in tenocytes when stimulated by proinflammatory cytokines or M1 macrophages (Mfs) (23,30). TNF-a treatment up-regulated expression of MMP-1, proinflammatory (e.g., TNF-a and IL-1b), and anti-inflammatory (e.g., IL-6 and IL-10) cytokines in human tenocytes (23). ASCs coculture with M1 Mfs successfully suppressed the effects of M1 Mfs on tenocytes by inducing a phenotypic switch from a proinflammatory Mf phenotype to an anti-inflammatory Mf phenotype (30).…”

Evidence of the TNF-α System in the Human Achilles Tendon: Expression of TNF-α and TNF Receptor at both Protein and mRNA Levels in the Tenocytes

“…Cultured avian tendon cells exposed to TNF-␣ , an increased temperature, and mechanical stress led to a reduction of procollagen mRNA expression [Pan and Halper, 2003]. Cultured human tenocytes treated with TNF-␣ reduced their type 1 collagen deposition and highly upregulated their expression of pro-and immunoregulatory cytokines [John et al, 2010], and culturing tendon explants in the presence of TNF-␣ led to upregulation of the expression of Toll-like receptor 2 mRNA [de Mos et al, 2009].…”