Interleukin 1 and tumor necrosis factor do not regulate protein balance in skeletal muscle

Abstract

Recent studies have claimed that interleukin 1-containing preparations increase skeletal protein degradation similar to that seen during infection and inflammation. However, preparations employed have contained other products of activated macrophages, including tumor necrosis factor-alpha. In the present report, we investigated the capability of recombinant-derived murine and human interleukins 1-alpha and 1-beta and human tumor necrosis factor-alpha to affect skeletal protein synthesis and degradation both in vitro and in vivo. Partially purified products of Staphylococcus albus-stimulated human blood monocytes increased skeletal protein degradation both in vivo and in vitro. However, none of the recombinant interleukin 1 nor the human tumor necrosis factor-alpha preparations had any impact on skeletal protein balance. Both recombinant interleukin 1 and tumor necrosis factor-alpha stimulated the production of prostaglandin E2 (PGE2). Furthermore, a polyclonal antibody to human interleukin 1 eliminated the lymphoproliferative response to partially purified monocyte preparations (interleukin 1 activity), but failed to abrogate the increased skeletal protein degradation in vitro. This study demonstrates that although interleukin 1 and tumor necrosis factor-alpha induce a PGE2 response by skeletal muscle in vitro, some macrophage product distinct from either interleukin 1 or tumor necrosis factor-alpha is responsible for the accelerated skeletal protein degradation seen with partially purified human blood monocyte products. Elevated PGE2 levels do not appear to regulate skeletal protein balance in vitro.

Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss

“…In a recent study by Beck and Tisdale (1987) evidence was presented that a 'muscle tissue proteoteolytic factor' is produced by a murine adenocarcinoma of the colon called MAC 16, a tumour selected for its ability to induce severe cachexia in mice. Further evidence that polypeptide factors with similar biological activity are produced by activated macrophages is presented here (Table I) and elsewhere Goldberg et al, 1988;Moldawer et al, 1987).…”

“…This protein secreted by activated monocytes may be IL-1 or a IL-i-like peptide (Baracos et al, 1983;Dinarello et al, 1984). It has also been shown that prostaglandin E2 production was increased by these macrophage secretory products and an inhibitor of the cycloocygenase pathway, indomethacin, partially attenuated the stimulation in skeletal muscle protein degradation (Baracos et al, 1983 (Moldawer et al, 1987;Goldberg et al, 1988). Likewise, the involvement of TNF-a on catabolism of proteins has been demonstrated by some studies in vivo (Warren et al, 1987;Flores et al, 1989;Fong et al, 1989) and in vitro Charters & Grimble, 1989) and refuted in others (Kettelhutt & Goldberg, 1988;Moldawer et al, 1987;Rofe et al, 1987;Michie et al, 1988).…”

“…It has also been shown that prostaglandin E2 production was increased by these macrophage secretory products and an inhibitor of the cycloocygenase pathway, indomethacin, partially attenuated the stimulation in skeletal muscle protein degradation (Baracos et al, 1983 (Moldawer et al, 1987;Goldberg et al, 1988). Likewise, the involvement of TNF-a on catabolism of proteins has been demonstrated by some studies in vivo (Warren et al, 1987;Flores et al, 1989;Fong et al, 1989) and in vitro Charters & Grimble, 1989) and refuted in others (Kettelhutt & Goldberg, 1988;Moldawer et al, 1987;Rofe et al, 1987;Michie et al, 1988). Nevertheless, the capacity of IL-1 and TNF to cause either weight loss or anorexia in animals has often been noted (Stovroff et al, 1988;Hellestein et al, 1989;Fong et al, 1989;Michie et al, 1988; (Dinarello et al, 1986a), and polyclonal rabbit anti-sera to rhIL-1-a and rhIL-1-P (Dinarello et al, 1986b) were generously provided by Dr Charles A. Dinarello, Tufts University/New England Medical Center (Boston, MA).…”

Mechanism of muscle protein degradation in cancer cachexia

“…Thus the accelerated breakdown of protein appeared to be mediated by IL-1 in co-operation with other unidentified factors. However, Moldawer et al (1987) have shown that neither TNF-a or IL-1 regulate protein balance in skeletal muscle in vitro. Also in the present study the serum proteolysis-inducing factor is stable to heating at 60°C for 5 min suggesting that it is not a cytokine.…”

TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation

“…Moreover, acute in vivo administration of TNF-␣ has been shown to impair amino acid uptake by muscle (2,57). However, subsequent investigations generally failed to detect significant alterations in either the rate of protein synthesis or protein degradation in response to the acute injection of TNF-␣ (8,25,40,46). More recently, Zamir et al (58) was able to demonstrate a significant increase in proteolysis and a tendency for a decrease in protein synthesis in skeletal muscle incubated in vitro 2 h after a single injection of TNF-␣.…”