Cytokine-Hormone Interactions: Tumor Necrosis Factor α Impairs Biologic Activity and Downstream Activation Signals of the Insulin-Like Growth Factor I Receptor in Myoblasts

Abstract

TNFalpha is elevated following damage to skeletal muscle. Here we provide evidence that TNFalpha acts on muscle cells to induce a state of IGF-I receptor resistance. We establish that TNFalpha inhibits IGF-I-stimulated protein synthesis in primary porcine myoblasts. Similar results were observed in C(2)C(12) murine myoblasts, where as little as 0.01 ng/ml TNFalpha significantly inhibits protein synthesis induced by IGF-I. TNFalpha also impairs the ability of IGF-I to induce expression of a key myogenic transcription factor, myogenin. The inhibition by TNFalpha of IGF-I-induced protein synthesis and expression of myogenin is not due to direct killing of myoblasts by TNFalpha. Although IGF-I induces an approximately 19-fold induction in tyrosine phosphorylation of the beta-chains of its receptor, TNFalpha does not inhibit this autophosphorylation. Instead, TNFalpha significantly reduces by approximately 50% IGF-I-stimulated tyrosine phosphorylation of two of the major downstream receptor docking molecules, insulin receptor substrate (IRS)-1 and IRS-2. These results establish that low picogram concentrations of TNFalpha acts on both porcine and murine myoblasts to impair tyrosine phosphorylation of both IRS-1 and IRS-2, but not the receptor itself. These data are consistent with the notion that very low physiological concentrations of TNFalpha interfere with both protein synthesis and muscle cell development by inducing a state of IGF-I receptor resistance.

Tumor Necrosis Factor α Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis

“…Consistent with the idea that the cytostatic properties of TNF␣ are detected only in the presence of IGF-I, we have identified IRS proteins as a direct target of TNF␣ in inhibiting IGF-I-induced neuroprotection (63), skeletal muscle protein synthesis (64), and breast cancer cell growth (6). In all these reports, TNF␣ consistently inhibits IGF-I-induced tyrosine phosphorylation of IRS proteins.…”

Tumour necrosis factor blockade did not prevent the increase of muscular muscle RING finger-1 and muscle atrophy F-box in arthritic rats

“…Since this is not the case, there is a possibility that arthritic muscles have become resistant to IGF-I, as has been observed in experimental models of sepsis (Fang et al 2000) and chronic renal failure (Ding et al 1996). This effect can be exerted by muscular TNF-a, since this cytokine acts on muscle cells inducing a state of IGF-I receptor resistance (Broussard et al 2003). Moreover, anti-TNF therapy improves glucocorticoid-induced IGF-I resistance in rheumatoid arthritis (Sarzi-Puttini et al 2006).…”

Novel activity of an anti-inflammatory cytokine: IL-10 prevents TNFα-induced resistance to IGF-I in myoblasts

“…TNFα is closely implicated in the pathophysiology of muscle wasting disorders and is thought to act in part by blocking the actions of growth factors such as IGF-I, thereby inducing hormone resistance (Broussard et al, 2003;Strle et al, 2004). Here we tested the possibility that IL-10 might overcome this type of hormone resistance.…”

“…These clinical disorders occur along with a decline in IGF-I anabolic activity, which is consistent with in vitro findings in muscle progenitor cells. Very low concentrations of TNFα (0.01-1 ng/ml) inhibit IGF-I-induced protein synthesis (Broussard et al, 2003;Strle et al, 2004) and expression of the critical muscle differentiation factors, MyoD and myogenin (Broussard et al, 2003;Strle et al, 2004). This ability of TNFα to induce hormone resistance is mediated by c-Jun N-terminal kinase (JNK) (Strle et al, 2006).…”