Monocyte p110α phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production

Abstract

Mononuclear phagocytes are critical modulators and effectors of innate and adaptive immune responses, and PI-3Ks have been shown to be multifunctional monocyte regulators. The PI-3K family includes eight catalytic isoforms, and only limited information is available about how these contribute to fine specificity in monocyte cell regulation. We examined the regulation of phagocytosis, the phagocyte oxidative burst, and LPS-induced cytokine production by human monocytic cells deficient in p110α PI-3K. We observed that p110α PI-3K was required for phagocytosis of IgG-opsonized and nonopsonized zymosan in differentiated THP-1 cells, and the latter was inhibitable by mannose. In contrast, p110α PI-3K was not required for ingestion serum-opsonized zymosan. Taken together, these results suggest that FcγR- and mannose receptor-mediated phagocytosis are p110α-dependent, whereas CR3-mediated phagocytosis involves a distinct isoform. It is notable that the phagocyte oxidative burst induced in response to PMA or opsonized zymosan was also found to be dependent on p110α in THP-1 cells. Furthermore, p110α was observed to exert selective and bidirectional effects on the secretion of pivotal cytokines. Incubation of p110α-deficient THP-1 cells with LPS showed that p110α was required for IL-12p40 and IL-6 production, whereas it negatively regulated the production of TNF-α and IL-10. Cells deficient in p110α also exhibited enhanced p38 MAPK, JNK, and NF-κB phosphorylation. Thus, p110α PI-3K appears to uniquely regulate important monocyte functions, where other PI-3K isoforms are uninvolved or unable to fully compensate.