Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation.

Abstract

The idiopathic inflammatory myopathies are characterized by antibody- or cell-mediated immune response against unknown muscle tissue antigens. In these diseases a cellular infiltrate, composed of T and B lymphocytes, macrophages and NK cells, may invade muscle tissue with a gradient from the perivascular space to the endomysial compartment. Muscle cells may be actively involved in the processes of mononuclear cell recruitment and activation from the blood stream to the areas of inflammation. In order to verify this hypothesis, cultured human myoblasts were tested for their capacity to express different pro-inflammatory cytokines [IL-1alpha, IL-1beta, IL-6 and tumor necrosis factor (TNF)-alpha] and chemokines (IL-8, MCP-1 and RANTES) at the mRNA level and protein secretion, in the presence of the pro-inflammatory cytokines IFN-gamma and TNF-alpha alone or in combination. We confirmed that human myoblasts expressed IL-1alpha and IL-6 constitutively, while IL-1beta and TNF-alpha are detected only after treatment with pro-inflammatory cytokines; moreover, we observed that TNF-alpha was expressed on an autocrine fashion by myoblasts. IL-8 and RANTES were expressed constitutively while MCP-1 after proper induction. These molecular data were further confirmed by specific ELISA in the supernatant from cultured myoblasts. Our results underline the importance of human myoblasts in the recruitment of leukocytes from the blood stream and, most probably, in the cross-talk between infiltrating inflammatory cells and muscle cells, creating the conditions for a chronic inflammation. Moreover, the capacity of muscle cells to behave as cells of the immune system has to be kept in mind, also in view of i.m. vaccination and use of molecular engineered myoblasts as vehicles in gene therapy.

Increased muscle interstitial levels of inflammatory cytokines in polymyalgia rheumatica

“…Although one study reported a modest infiltration of lymphocytes (3), subsequent histologic studies have failed to demonstrate interstitial infiltration of inflammatory cells in PMR. Interestingly, other studies have shown that the cytokines measured in the present study are released from myoblasts and fibroblasts (38). Furthermore, in response to exercise, IL-6 may be released from myocytes and interstitial fibroblasts (39,40), and IL-8 may be released from myocytes (41).…”

Skeletal muscle cells: from local inflammatory response to active immunity

“…50 In human myoblasts, the induction of membrane and soluble ICAM-1 expression can be downregulated by TGF-b and IL-10, suggesting that these two cytokines can attain their inhibitory effect, influencing the ongoing inflammatory process in muscle, through modulation of adhesion molecules (Figure 2b). 51 Chemokine expression in inflammatory myopathies, 38 along with experimental in vitro results showing the effect of different cytokines on chemokine profile in myoblasts, confirms the importance of muscle cells in local leukocyte recruitment: 40 myoblast stimulation with IL-1b, IFN-g and TNF-a induces, with distinct kinetics, expression of the neutrophil-attracting IL-8, as well as of MCP-1, MIP-1a, MIP-3a and RANTES, acting mainly on lymphocytes and monocytes. Among these chemokines, IL-8 has a relatively unique and important role, as it is produced in the early stages of the inflammatory response, but it persists for a prolonged period of time, even for days and weeks; 52 this kinetics distinguishes it from most of the other (Figure 3a).…”

Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis

“…Mouse CX3CR1 lo /Ly-6C + MOs and their human analogues bear several chemokine receptors, including CC chemokine receptor (CCR) 2, CCR1, CCR4, CCR7, CXC chemokine receptor 1, and CXC chemokine receptor 2 (9). The corresponding chemokines are expressed by muscle tissue during the fi rst days after injury (the cytokine expression profi le is available at http://pepr .cnmcresearch.org) (22,49,50). Monocyte chemoattractant protein-1 has been particularly involved in MO recruitment by injured muscle (19,20).…”