Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats

Tissue protein hypercatabolism (TPH) is an important feature in cancer cach exia, particularly with regard to the skeletal muscle. The Yoshida AH-130 r at ascites hepatoma is a model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the hos t a rapid and progressive muscle wasting, primarily due to TPH. The present study was aimed at investigating if IL-15, which is known to favour muscle fibre hypertrophy, could antagonize the enhanced muscle protein breakdown in this cancer cachexia model. Indeed, IL-15 treatment partly inhibited ske letal muscle wasting in AH-130-bearing rats by decreasing (8-fold) protein degradative rates las measured by C-14-bicarbonate pre-loading of muscle pr oteins) to values even lower than those observed in non-tumour-bearing anim als. These alterations in protein breakdown rates were associated with an i nhibition of the ATP-ubiquitin-dependent proteolytic pathway (35% and 41% f or 2.4 and 1.2 kb ubiquitin mRNA, and 57% for the C8 proteasome subunit, re spectively). The cytokine did not modify the plasma levels of corticosteron e and insulin in the tumour hosts. The present data give new insights into the mechanisms by which IL-15 exerts its preventive effect on muscle protei n wasting and seem to warrant the implementation of experimental protocols involving the use of the cytokine in the treatment of pathological states c haracterized by TPH, particularly in skeletal muscle, such as in the presen t model of cancer cachexia. (C) 2000 Cancer Research Campaign.