Activation of the PI3K pathway increases TLR-induced TNF-α and IL-6 but reduces IL-1β production in mast cells

Cell Signal. 2011 May;23(5):866-75. doi: 10.1016/j.cellsig.2011.01.012. Epub 2011 Jan 22.


Recognition of bacterial constituents by mast cells (MCs) is dependent on the presence of pattern recognition receptors, such as Toll-like receptors (TLRs). The final cellular response, however, depends on the influence of multiple environmental factors. In the current study we tested the hypothesis that the PI3K-activating ligands insulin-like growth factor-1 (IGF-1), insulin, antigen, and Steel Factor (SF) are able to modulate the TLR4-mediated production of proinflammatory cytokines in murine MCs. Costimulation with any of these ligands caused increased LPS-triggered secretion of IL-6 and TNF-α, but attenuated the production of IL-1β, though all three cytokines were produced in an NFκB-dependent manner. The pan-specific PI3K-inhibitor Wortmannin reverted the altered production of these cytokines. In agreement, MCs deficient for SHIP1, a negative regulator of the PI3K pathway, showed augmented secretion of IL-6/TNF-α and reduced production of IL-1β in response to LPS alone. The differential effects of IGF-1 on TLR4-mediated cytokine production were also observed in the context of TLR2 and IL-33 receptor-mediated MC activation. Importantly, these effects were seen in both bone marrow-derived and peritoneal MCs, suggesting general relevance for MCs. Using pharmacological and genetic tools, we could show that the p110δ isoform of PI3K is strongly implicated in SF-triggered suppression of LPS-induced IL-1β production. Costimulation with antigen was affected to a lesser extent. In conclusion, NFκB-dependent production of proinflammatory cytokines in MCs is differentially controlled by PI3K-activating ligand/receptor systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Inositol Polyphosphate 5-Phosphatases
  • Insulin-Like Growth Factor I / pharmacology
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-1beta / metabolism*
  • Interleukin-6 / metabolism*
  • Lipopolysaccharides / toxicity
  • Mast Cells / drug effects
  • Mast Cells / enzymology
  • Mast Cells / immunology*
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Receptors, Interleukin / metabolism
  • Signal Transduction
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptors / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Il1rl1 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-1beta
  • Interleukin-6
  • Lipopolysaccharides
  • Receptors, Interleukin
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • Inpp5d protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases