Gap junctions in IL-1β-mediated cell survival response to strain

Qi J, Chi L, Bynum D, Banes AJ. Gap junctions in IL-1 beta-mediated cell survival response to strain. J Appl Physiol 110: 1425-1431, 2011. First published January 6, 2011; doi: 10.1152/japplphysiol.00477.2010.Mechanical stimuli play important roles in proliferation and differentiation of connective tissue cells, and development and homeostatic maintenance of tissues. However, excessive mechanical loading to a tissue can injure cells and disrupt the matrix, as occurs in tendinopathy. Tendinopathy is a common clinical problem in athletes and in many occupational settings due to overuse of the tendon. Moreover, interleukin (IL)-1 beta is generally considered to be a bad cytokine, activating NF-kappa b and cell death and inducing matrix metalloproteinase (MMPs 1, 2, 3) expression and matrix destruction. However, activated NF-kappa B can also drive a cell survival pathway. We have reported that cyclic strain induced tenocyte death in three-dimensional (3D) cultures, and IL-1 beta could promote cell survival under strain. Therefore, it was hypothesized that 1) cyclic strain could induce cell death in tenocytes as observed in pathologic tendons in vivo; 2) a gene expression profile indicative of tendinopathy could be identified; and 3) low-dose IL-1 beta could protect cells from strain-induced, tendinopathy-like changes. Human tenocytes were cultured in 3D type I collagen hydrogels and subjected to 3.5% elongation at 1 Hz for 1 h/day for up to 5 days with or without IL-1 beta. Real-time RT-PCR data showed that cyclic strain regulated the expression of tendinopathy marker genes in a manner similar to that found in pathological tendons from patients and that addition of IL-1 beta reversed the gene expression changes to control levels. Results of further studies showed that IL-1 beta may modulate cell survival through upregulating the expression of connexin 43, which is involved in the modulation of cell death/survival in a variety of cells and tissues. The elucidation of the mechanisms underlying strain-induced cell death and recovery from strain injury will facilitate our understanding of the pathogenesis of tendinopathy and may lead to the discovery of new molecular targets for early diagnosis and treatment of tendinopathy.