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 LPSinduced cytokine production by human monocytic cells deficient in p110␣ PI-3K. We observed that p110␣ 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, p110␣ PI-3K was not required for ingestion serum-opsonized zymosan. Taken together, these results suggest that Fc␥R-and mannose receptor-mediated phagocytosis are p110␣-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 p110␣ in THP-1 cells. Furthermore, p110␣ was observed to exert selective and bidirectional effects on the secretion of pivotal cytokines. Incubation of p110␣-deficient THP-1 cells with LPS showed that p110␣ was required for IL-12p40 and IL-6 production, whereas it negatively regulated the production of TNF-␣ and IL-10. Cells deficient in p110␣ also exhibited enhanced p38 MAPK, JNK, and NF-B phosphorylation. Thus, p110␣ PI-3K appears to uniquely regulate important monocyte functions, where other PI-3K isoforms are uninvolved or unable to fully compensate. J. Leukoc. Biol. 81: 1548 -1561; 2007.

Shiga Toxin 1-Induced Proinflammatory Cytokine Production Is Regulated by the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Pathway

“…Moreover, the kinase inhibitors alone modestly increased TNF-␣ and IL-1␤ production. Thus, our findings are in accordance with those of earlier studies showing that inhibition of the PI3K/Akt pathway increased cytokine and tissue factor expression induced by LPS treatment of murine and human macrophages (18,26,29), and activation of the PI3K/Akt pathway by insulin reduced inflammation in mice administered LPS (24). A number of mechanisms may be contributing to PI3K/Akt-mediated negative regulation of cytokine expression.…”

PI3K p110β Positively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages and Dendritic Cells and JNK1 Plays a Novel Role

“…These results are consistent with the recent reports by Lee et al (21). They demonstrated that a deficiency in PI3K p110␣ in THP-1 monocytic cells suppressed IL-12p40 protein production and mRNA expression induced by LPS (21). On the other hand, PI3K p110␣ siRNA significantly suppressed IL-12 protein production, while it had little effect on IL-12 mRNA expression in MD-DCs (Fig.…”

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation

“…IкB kinase regulatory subunit ERC1 is required for NFкB activation (Ducut Sigala et al 2004), and CARM1/PRMT4 has been shown to function as a promoter-specific NFкB regulator (Covic et al 2005). In monocytes and macrophages, LPS is implicated in PIK3 and AKT pathway activation (Guha and Mackman 2002;Lee et al 2007). In monocytes, a dependence of LPS-induced AKT activation on class I A of the three PIK3 classes (Cantley 2002) has been shown by RNAi-mediated PIK3CA silencing (Lee et al 2007).…”

“…In monocytes and macrophages, LPS is implicated in PIK3 and AKT pathway activation (Guha and Mackman 2002;Lee et al 2007). In monocytes, a dependence of LPS-induced AKT activation on class I A of the three PIK3 classes (Cantley 2002) has been shown by RNAi-mediated PIK3CA silencing (Lee et al 2007). In contrast, RIP-Chip experiments with untreated macrophages and after LPS-activation employing an antibody against TTP revealed that TTP modulates the inflammatory response by controlling the stability of mRNAs, which encode pro-and antiinflammatory cytokines (Stoecklin et al 2008;Kratochvill et al 2011).…”