Trends in Immunology
Volume 29, Issue 10, October 2008, Pages 493-501
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Review
The multiple roles of phosphoinositide 3-kinase in mast cell biology

https://doi.org/10.1016/j.it.2008.07.004Get rights and content

Mast cells play a central role in the initiation of inflammatory responses associated with asthma and other allergic disorders. Receptor-mediated mast cell growth, differentiation, homing to their target tissues, survival and activation are all controlled, to varying degrees, by phosphoinositide-3-kinase (PI3K)-driven pathways. It is not fully understood how such diverse responses can be differentially regulated by PI3K. However, recent studies have provided greater insight into the mechanisms that control, and those that are controlled by, different PI3K subunit isoforms in mast cells. In this review, we discuss how PI3K influences the mast cell processes described above. Furthermore, we describe how different mast cell receptors use alternative isoforms of PI3K for these functions and discuss potential downstream targets of these isoforms.

Section snippets

Regulation of mast cell processes by Kit and FcɛRI

Mast cells are important effector cells that contribute to the body's ability to respond defensively to invading pathogens and parasites 1, 2. However, activation of mast cells can have disabling consequences by initiating allergic inflammatory reactions in response to antigen that are associated with atopic asthma, allergic rhinitis, eczema and anaphylaxis [3]. In addition, mast cells have also been implicated in rheumatoid arthritis, multiple sclerosis, atherosclerosis, inflammatory bowel

Expression and regulation of PI3K in mast cells

PI3Ks comprise a family of lipid kinases (Box 2) that play crucial roles in multiple biological responses 11, 12, 13. Class 1 PI3Ks, the major hematopoietic forms of PI3K (Figure 1; Box 2), are heterodimeric comprising a regulatory and catalytic subunit. Mast cells express the class 1A p85α, p85β and p50α regulatory subunit isoforms 14, 15 in addition to all three class 1A PI3K catalytic subunit isoforms, p110α, p110β, and p110δ and the class 1B p110γ catalytic subunit 16, 17 (Figure 1). As Kit

Mast cell degranulation and cytokine production

A role for PI3K in mast cell activation has been revealed by several approaches as outlined in Box 3. The PI3K inhibitors, wortmannin and LY294002, have been widely reported to inhibit antigen-mediated degranulation and cytokine production in both rodent and human mast cells 14, 32, 39. However, at least in human mast cells, these compounds fail to completely inhibit degranulation suggesting that, although PI3K is essential for optimal degranulation of mast cells, PI3K-independent pathways

Negative regulation of PI3K-dependent mast cell responses by PTEN and SHIP

PtdInsP3 levels, and hence PI3K-regulated signaling pathways in mast cells and other cell types, are finely regulated by the balance between phosphorylation induced by PI3Ks and dephosphorylation regulated by the inositol phosphatases, PTEN and SHIP (Box 2; Figure 2b). In quiescent human mast cells, shRNA-induced knockdown of PTEN results in increased basal PtdInsP3 levels and constitutive phosphorylation of AKT and the mitogen-activated protein (MAP) kinases, p38 and c-Jun N-terminal kinase

Downstream effectors regulated by PI3K

The above discussions demonstrate that PI3K regulates diverse responses in activated mast cells. From studies conducted in multiple cell types, it is evident that PI3K can influence a wide range of signaling molecules and pathways [57]. Systematic studies, using a variety of approaches (Box 3), are now beginning to address which of these PI3K-regulated signaling processes regulate specific mast cell responses. In the following section and in Figure 3, we describe what is currently known about

Summary, conclusions and future considerations

In summary, it is now clear that PI3K-regulated signaling events play a central role in mast cell biology. The downstream targets responsible for the receptor-mediated, PI3K-dependent responses in mast cells have still not been fully elucidated. However, PI3K-regulated degranulation, and to a certain extent cytokine production, seems to be linked to the regulation of a latent calcium signal, likely requiring activation of Btk. Multiple PI3K-regulated processes seem to contribute to mast cell

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgements

Research in the authors’ laboratory is supported by the NIAID Intramural Program within the National Institutes of Health. The authors thank Michael A. Beaven LMI/NHLBI/NIH for critical review of the manuscript and the editor and the reviewers of this manuscript for helpful comments. Because of space constraints, not all pertinent literature could be referenced in this article. This does not imply that other articles not referenced are of lesser merit.

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