Isovalerylcarnitine regulates immune function and apoptosis of U937 myeloid leukemic cells

Isovalerylcarnitine is part of the pool of carnitine forms. In mitochondria it takes part in many well known activities of carnitine and its short-chain esters. However, this compound also performs activities that distinguish it from the other carnitine esters, especially its ability to inhibit proteolytic enzymes, activating the calpain system. Both the calpain and the caspase systems belong to the protease family and lead to cytochrome activation and apoptosis. The two systems can interact to promote apoptosis. In view of this pro-apoptotic activity of isovalerylcarnitine, studies were carried out to ascertain whether this carnitine derivative influences cell-reaction processes associated with apoptosis. U937 leukemic cells were selected for these studies because they are a well established model for the assessment of cellular immune responses. Besides nuclear morphologic alterations produced by apoptosis that can be detected by specific histochemical and microscopic methods, we also took other cell functions into consideration, such as phagocytosis, cell killing and cell growth, which are indices of immune function related to apoptosis. Unlike reference carnitine forms, isovalerylcarnitine produced an early and marked increase in phagocytosis and also an increase in cell killing. Cell proliferation was reduced. The hypothesis is set forth that isovalerylcarnitine may be a caspase-activating, pro-apoptotic factor that resembles various anti-cancer agents, which induce early apoptosis that coincides with early activation of caspase. This hypothesis is supported by the ability of isovalerylcarnitine to induce early phagocytosis and cell killing.