Partially distinct molecular mechanisms mediate inhibitory FcgammaRIIB signaling in resting and activated B cells

J Immunol. 2001 Jul 1;167(1):204-11. doi: 10.4049/jimmunol.167.1.204.

Abstract

FcgammaRIIB functions as an inhibitory receptor to dampen B cell Ag receptor signals and immune responses. Accumulating evidence indicates that ex vivo B cells require the inositol 5-phosphatase, Src homology domain 2-containing inositol 5-phosphatase (SHIP), for FcgammaRIIB-mediated inhibitory signaling. However, we report here that LPS-activated primary B cells do not require SHIP and thus differ from resting B cells. SHIP-deficient B cell blasts display efficient FcgammaRIIB-dependent inhibition of calcium mobilization as well as Akt and extracellular signal-related protein kinase phosphorylation. Surprisingly, FcgammaRIIB-dependent degradation of phosphatidylinositol 3,4,5-trisphosphate and conversion into phosphatidylinositol 3,4-bisphosphate occur in SHIP-deficient B cell blasts, demonstrating the function of an additional inositol 5-phosphatase. Further analysis reveals that while resting cells express only SHIP, B cell blasts also express the recently described inositol 5-phosphatase, SHIP-2. Finally, data suggest that both SHIP-2 and SHIP can mediate downstream biologic consequences of FcgammaRIIB signaling, including inhibition of the proliferative response.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / physiology*
  • B-Lymphocytes / cytology
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / immunology*
  • Calcium / antagonists & inhibitors
  • Calcium / physiology
  • Calcium Signaling / genetics
  • Calcium Signaling / immunology
  • Interphase / genetics
  • Interphase / immunology
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation* / genetics
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol Phosphates / antagonists & inhibitors
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphatidylinositol Phosphates / physiology
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / biosynthesis
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / physiology
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor Aggregation / immunology
  • Receptors, Antigen, B-Cell / antagonists & inhibitors
  • Receptors, Antigen, B-Cell / physiology
  • Receptors, IgG / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • src Homology Domains / genetics
  • src Homology Domains / immunology

Substances

  • Antigens, CD
  • Fc gamma receptor IIB
  • Lipopolysaccharides
  • Phosphatidylinositol Phosphates
  • Proto-Oncogene Proteins
  • Receptors, Antigen, B-Cell
  • Receptors, IgG
  • phosphatidylinositol 3,4,5-triphosphate
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Phosphoric Monoester Hydrolases
  • INPPL1 protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Calcium