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  SHIP Down-Regulates FcεR-1-Induced Degranulation at Supraoptimal IgE or Antigen Levels

Gimborn, K., Lessmann, E., Kuppig, S., Krystal, G., & Huber, M. (2005). SHIP Down-Regulates FcεR-1-Induced Degranulation at Supraoptimal IgE or Antigen Levels. The Journal of Immunology, 174, 507-516.

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 Creators:
Gimborn, Kerstin1, Author              
Lessmann, Eva1, Author              
Kuppig, Stephan1, Author              
Krystal, Gerald1, Author              
Huber, Michael1, Author              
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1Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243645              

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 Abstract: Cross-linking of the IgE-loaded high-affinity IgE receptor (FcεR1) by multivalent Ags results in mast cell activation and subsequent release of multiple proinflammatory mediators. The dose-response curve for FcεR1-mediated degranulation is bell-shaped, regardless of whether the IgE or the Ag concentration is varied. Although overall calcium influx follows this bell-shaped curve, intracellular calcium release continues to increase at supraoptimal IgE or Ag concentrations. As well, overall calcium mobilization adopts more transient kinetics when stimulations are conducted with supraoptimal instead of optimal Ag concentrations. Moreover, certain early signaling events continue to increase whereas degranulation drops under supraoptimal conditions. We identified SHIP, possibly in association with the FcεR1 β-chain, as a critical negative regulator acting within the inhibitory (supraoptimal) region of the dose-response curve that shifts the kinetics of calcium mobilization from a sustained to a transient response. Consistent with this, we found that degranulation of SHIP-deficient murine bone marrow-derived mast cells was not significantly reduced at supraoptimal Ag levels. A potential mediator of SHIP action, Bruton's tyrosine kinase, did not seem to play a role within the supraoptimal suppression of degranulation. Interestingly, SHIP was found to colocalize with the actin cytoskeleton (which has been shown previously to mediate the inhibition of degranulation at supraoptimal Ag doses). These results suggest that SHIP, together with other negative regulators, restrains bone marrow-derived mast cell activation at supraoptimal IgE or Ag concentrations in concert with the actin cytoskeleton.

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Language(s): eng - English
 Dates: 2005
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: eDoc: 261788
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Title: The Journal of Immunology
Source Genre: Journal
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Pages: - Volume / Issue: 174 Sequence Number: - Start / End Page: 507 - 516 Identifier: -