FcgammaR-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and/or Ras/Erk pathways.
Phagocytosis of IgG-coated particles via FcgammaR is accompanied by the generation of superoxide and inflammatory cytokines, which can cause collateral tissue damage in the absence of regulation. Molecular mechanisms regulating these phagocytosis-associated events are not known. SHIP is an inositol phosphatase that downregulates PI3K-mediated activation events. Here, we have examined the role of SHIP in FcgammaR-induced production of superoxide and inflammatory cytokines. We report that primary SHIP-deficient bone marrow macrophages produce elevated levels of superoxide upon FcgammaR clustering. Analysis of the molecular mechanism revealed that SHIP regulates upstream Rac-GTP binding, an obligatory event for superoxide production. Likewise, SHIP-deficient macrophages displayed enhanced IL-1beta and IL-6 production in response to FcgammaR clustering. Interestingly, whereas IL-6 production required activation of both PI3K and Ras/Erk pathways, IL-1beta production was dependent only on Ras/Erk activation, suggesting that SHIP may also regulate the Ras/Erk pathway in macrophages. Consistently, SHIP-deficient macrophages displayed enhanced activation of Erk upon FcgammaR clustering. Inhibition of Ras/Erk or PI3K suppressed the enhanced production of IL-6 in SHIP-deficient macrophages. In contrast, inhibition of Ras/Erk, but not PI3K, suppressed IL-1beta production in these cells. Together, these data demonstrate that SHIP regulates phagocytosis-associated events through the inhibition of PI3K and Ras/Erk pathways.
Department of Internal Medicine, The Ohio State University Biochemistry Program, Columbus, USA.
Latha P
LP
Ganesan
Trupti
T
Joshi
Huiqing
H
Fang
Vijay Kumar
VK
Kutala
Julie
J
Roda
Rossana
R
Trotta
Amy
A
Lehman
Periannan
P
Kuppusamy
John C
JC
Byrd
William E
WE
Carson
Michael A
MA
Caligiuri
Susheela
S
Tridandapani
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D017452:Receptors, IgG; D013481:Superoxides; D019869:Phosphatidylinositol 3-Kinases; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins