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Published online before print March 16, 2007

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(Journal of Leukocyte Biology. 2007;81:1548-1561.)
© 2007 by Society for Leukocyte Biology

Monocyte p110 phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production

Jimmy S. Lee^*,, William M. Nauseef, Alireza Moeenrezakhanlou^*,, Laura M. Sly^,||, Sanaa Noubir^*,, Kevin G. Leidal, Jamie M. Schlomann, Gerald Krystal^,|| and Neil E. Reiner^*,,¶,1

Vancouver Coastal Health Research Institute (VCHRI) and Departments of
^* Medicine (Division of Infectious Diseases),
^¶ Microbiology and Immunology, Faculties of Medicine and Science, and
Pathology, University of British Columbia, and
^|| Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and
Inflammation Program and Department of Medicine, University of Iowa, Veterans Administration Medical Center, Iowa City, Iowa, USA

¹ Correspondence: Division of Infectious Diseases, University of British Columbia, Rm. 452D, 2733 Heather St., Vancouver, BC, Canada, V5Z 3J5. E-mail: ethan{at}interchange.ubc.ca

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 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 FcR- 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.

Key Words: PI-3K • mannose • Fc receptor • complement receptor 3 • lentivirus • siRNA

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