Monocyte p110alpha phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production.
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 p110alpha PI-3K. We observed that p110alpha 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, p110alpha PI-3K was not required for ingestion serum-opsonized zymosan. Taken together, these results suggest that FcgammaR- and mannose receptor-mediated phagocytosis are p110alpha-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 p110alpha in THP-1 cells. Furthermore, p110alpha was observed to exert selective and bidirectional effects on the secretion of pivotal cytokines. Incubation of p110alpha-deficient THP-1 cells with LPS showed that p110alpha was required for IL-12p40 and IL-6 production, whereas it negatively regulated the production of TNF-alpha and IL-10. Cells deficient in p110alpha also exhibited enhanced p38 MAPK, JNK, and NF-kappaB phosphorylation. Thus, p110alpha PI-3K appears to uniquely regulate important monocyte functions, where other PI-3K isoforms are uninvolved or unable to fully compensate.
Lee
Jimmy S
JS
Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia, Rm. 452D, 2733 Heather St., Vancouver, BC, Canada, V5Z 3J5.
Nauseef
William M
WM
Moeenrezakhanlou
Alireza
A
Sly
Laura M
LM
Noubir
Sanaa
S
Leidal
Kevin G
KG
Schlomann
Jamie M
JM
Krystal
Gerald
G
Reiner
Neil E
NE
D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis*; D004789:Enzyme Activation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D037181:Lectins, C-Type / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000502:physiology; D008358:Mannose / Q000494:pharmacology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000502:physiology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D010088:Oxidoreductases / Q000378:metabolism*; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology; D016897:Respiratory Burst; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology; D015054:Zymosan / Q000276:immunology / Q000494:pharmacology
D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D007074:Immunoglobulin G; D007527:Isoenzymes; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D008358:Mannose; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010088:Oxidoreductases; D019869:Phosphatidylinositol 3-Kinases; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D051197:Toll-Like Receptor 4; D015054:Zymosan; C495345:TLR4 protein, human; C497132:PIK3CB protein, human