Stimulation of Muscle Protein Degradation and Prostaglandin E₂Release by Leukocytic Pyrogen (Interleukin-1)

Abstract

To clarify the mechanisms underlying the loss of body protein during fever and sepsis, we incubated rat muscles with highly purified human leukocytic pyrogen. This polypeptide, which appears identical to interleukin-1, is released by leukocytes and signals the onset of fever in the hypothalamus. In muscles incubated at 37 degrees C, leukocytic pyrogen stimulated net protein degradation by 62 to 118 per cent (P less than 0.001). Proteolysis increased, but rates of muscle-protein synthesis did not change. The pyrogen also dramatically stimulated muscle synthesis of prostaglandin E2, which promotes protein breakdown in this tissue. Addition of indomethacin with leukocytic pyrogen prevented prostaglandin E2 synthesis and abolished the increase in proteolysis. The acceleration of protein breakdown induced by pyrogen was also blocked by Ep-475, an inhibitor of lysosomal thiol proteases. When muscles were incubated at 39 degrees C to mimic fever, protein breakdown increased, but addition of leukocytic pyrogen caused a further marked increase in proteolysis and prostaglandin E2 production. Thus, human leukocytic pyrogen can act on skeletal muscle to stimulate intralysosomal proteolysis by increasing the production of prostaglandin E2. These findings suggest that cyclooxygenase inhibitors may be useful in the treatment of negative nitrogen balance in fever. In addition, the release of prostaglandin E2 induced by leukocytic pyrogen may account for the myalgia that accompanies fever.

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

“…Recent studies have revealed that mobilisation of amino acids from skeletal muscle tissue of patients undergoing infectious illness, trauma or sepsis is mediated by a hormone-like protein called proteolysis-inducing factor (PIF) (Clowes et al, 1983). 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).…”

“…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).…”

“…In fact, we detected moderate levels of IL-1-P in six of the 20 plasma samples from cancer patients. IL-1 and an IL-1-derived fragment may be the causative agents of accelerated skeletal muscle protein catabolism in febrile patients (Clowes et al, 1983;Baracos et al, 1983;Dinarello et al, 1984). In agreement with these reports, it was shown here that recombinant human IL-1-o and IL-1-P can stimulate protein catabolism in a rat-diaphragm muscle bioassay.…”

Sarcopenia and its implications for the elderly

“…Activation of the immune system leads to production of in¯ammatory cytokines such as interleukin-1b (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6), which can cause amino acid export from muscle (Baracos et al, 1983;Clowes et al, 1983;Tsujinaka et al, 1996). Such a situation has been clearly demonstrated for acute illness and for chronic in¯ammatory conditions such as rheumatoid arthritis and HIV infection (Roubenoff et al, 1994).…”

Psychoneuroimmunology: The interface between behavior, brain, and immunity.

“…At the cellular level, IL-1 promotes the breakdown of muscle protein into amino acids (Baracos, Rodemann, Dinarello, & Goldberg, 1983), a process that is responsible for the muscle soreness experienced during infection. IL-1 also increases the availability of glucose for metabolism by peripheral tissues and the release of fatty acids from fat stores for similar use.…”