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Src family kinases and lipid mediators in control of allergic inflammation

Juan Rivera1, Ana Olivera

  • 1Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA. juan_rivera@nih.gov

Immunological Reviews
|May 15, 2007
PubMed

Insights

Src kinases Fyn and Lyn regulate mast cell responses by controlling lipid messengers like PIP(3) and S1P. Their levels impact degranulation and cytokine production, crucial for allergic reactions.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Src family kinases, Fyn and Lyn, are key regulators of Fc epsilon RI signaling in mast cells.
  • Lipid metabolites, particularly phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), critically influence mast cell activation.
  • Sphingosine kinases (SphK) produce sphingosine-1-phosphate (S1P), impacting mast cell migration and degranulation.

Purpose of the Study:

  • To elucidate the role of Src family kinases (Fyn and Lyn) in modulating mast cell responses.
  • To investigate the connection between Src kinases and lipid second messengers (PIP(3), S1P) in mast cell function.
  • To understand how these signaling pathways influence allergic responses.

Main Methods:

  • Utilized genetic models (e.g., SHIP-1(-/-), Lyn(-/-), Fyn(-/-) mast cells) to study kinase and phosphatase function.
  • Analyzed intracellular levels of PIP(3) and S1P in response to Fc epsilon RI engagement.
  • Investigated the impact of altered lipid metabolite levels on mast cell degranulation, cytokine production, and chemotaxis.

Main Results:

  • Fyn and Lyn activity dictates mast cell responsiveness by controlling PIP(3) levels, with altered levels leading to hyper- or hypodegranulation.
  • Downregulation of PTEN (phosphatase and tensin homologue deleted on chromosome 10) resulted in constitutive cytokine production, highlighting PIP(3) sensitivity.
  • Sphingosine-1-phosphate (S1P) produced by SphKs is essential for mast cell chemotaxis and degranulation, both in vitro and in vivo.

Conclusions:

  • Src family kinases (Fyn, Lyn) are critical upstream regulators of lipid second messenger pathways in mast cells.
  • The balance of PIP(3) and S1P levels, modulated by Src kinases, is fundamental to mast cell function and allergic responses.
  • Targeting these Src kinase-lipid messenger interactions may offer therapeutic strategies for allergic diseases.

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