Immunosuppressive mechanisms in protein-calorie malnutrition

Protein-calorie malnutrition (PCM) induces immunosuppression leading to increased mortality rates. Impaired macrophage respiratory burst activity (superoxide anion [O₂-] generation) occurs in PCM, but cellular mechanisms are unclear. The major pathway resulting in O₂- production involves inositol lipid-dependent signal transduction. This study examined the effect of mild versus severe PCM on macrophage O₂- generating signal transduction pathways specific for responses to Candida albicans. Mice (CFW/Swiss Webster: n = 300) were randomized to either control or low protein diets for 3 or 8 weeks. Peritoneal macrophages were harvested for O₂- production, mannose-fucose receptor (MFR) expression, membrane phospholipid analysis, arachidonic acid (AA) content, prostaglandin E₂ (PGE₂) production, and protein kinase C levels. O₂- release was impaired in both mild and severe PCM. MFR expression was also decreased at these time points. Inositol lipid content was significantly lower at the 8-week time point only, although PGE₂ and AA were significantly higher in the low protein diet group at 3 weeks. Protein kinase C levels were unchanged by PCM. Thus, mild PCM significantly increases macrophage-PGE₂ production secondary to increased AA phospholipid content, with subsequent inhibition of O₂- and MFR expression. Severe PCM inhibits macrophage (O₂-) through depletion of critical membrane phospholipid components with subsequent impairment in signal transduction.