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01-03-2009

Amplification mechanisms for the enhancement of antigen-mediated mast cell activation

Authors: Alasdair M. Gilfillan, Richard D. Peavy, Dean D. Metcalfe

Published in: Immunologic Research | Issue 1-3/2009

Abstract

Activation of mast cells in the allergic inflammatory response occurs via the high affinity receptor for IgE (FcεRI) following receptor aggregation induced by antigen-mediated cross-linking of IgE-occupied FcεRI. Recent observations suggest this response is profoundly influenced by other factors that reduce the threshold for, and increase the extent of, mast cell activation. For example, under experimental conditions, cell surface receptors such as KIT and specific G protein-coupled receptors synergistically enhance FcεRI-mediated mast cell degranulation and cytokine production. Activating mutations in critical signaling molecules may also contribute to such responses. In this review, we describe our research exploring the mechanisms regulating these synergistic interactions and, furthermore, discuss the relevance of our observations in the context of clinical considerations.

Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112:946–56.PubMedCrossRef

Mekori YA, Metcalfe DD. Mast cells in innate immunity. Immunol Rev. 2000;173:131–40.PubMedCrossRef

Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol. 2004;4:787–99.PubMedCrossRef

Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nat Immunol. 2005;6:135–42.PubMedCrossRef

Tkaczyk C, Jensen BM, Iwaki S, Gilfillan AM. Adaptive and innate immune reactions regulating mast cell activation: from receptor-mediated signaling to responses. Immunol Allergy Clin North Am. 2006;26:427–50.PubMedCrossRef

Gomi K, Zhu FG, Marshall JS. Prostaglandin E₂ selectively enhances the IgE-mediated production of IL-6 and granulocyte-macrophage colony-stimulating factor by mast cells through an EP1/EP3-dependent mechanism. J Immunol. 2000;165:6545–52.PubMed

Laffargue M, Calvez R, Finan P, Trifilieff A, Barbier M, Altruda F, et al. Phosphoinositide 3-kinase γ is an essential amplifier of mast cell function. Immunity. 2002;16:441–51.PubMedCrossRef

Qiao H, Andrade MV, Lisboa FA, Morgan K, Beaven MA. FcεR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood. 2006;107:610–8.PubMedCrossRef

Tkaczyk C, Horejsi V, Iwaki S, Draber P, Samelson LE, Satterthwaite AB, et al. NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and FcεRI aggregation. Blood. 2004;104:207–14.PubMedCrossRef

10.

Hundley TR, Gilfillan AM, Tkaczyk C, Andrade MV, Metcalfe DD, Beaven MA. Kit and FcεRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells. Blood. 2004;104:2410–7.PubMedCrossRef

11.

Iwaki S, Tkaczyk C, Satterthwaite AB, Halcomb K, Beaven MA, Metcalfe DD, et al. Btk plays a crucial role in the amplification of FcεRI-mediated mast cell activation by kit. J Biol Chem. 2005;280:40261–70.PubMedCrossRef

12.

Gilfillan AM, Tkaczyk C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol. 2006;6:218–30.PubMedCrossRef

13.

Rivera J, Gilfillan AM. Molecular regulation of mast cell activation. J Allergy Clin Immunol. 2006;117:1214–25.PubMedCrossRef

14.

Kuehn HS, Gilfillan AM. G protein-coupled receptors and the modification of FcεRI-mediated mast cell activation. Immunol Lett. 2007;113:59–69.PubMedCrossRef

15.

Kuehn HS, Beaven MA, Ma HT, Kim MS, Metcalfe DD, Gilfillan AM. Synergistic activation of phospholipases Cγ and Cβ: a novel mechanism for PI3K-independent enhancement of FcepsilonRI-induced mast cell mediator release. Cell Signal. 2008;20:625–36.PubMedCrossRef

16.

Toda M, Dawson M, Nakamura T, Munro PM, Richardson RM, Bailly M, et al. Impact of engagement of FcεRI and CC chemokine receptor 1 on mast cell activation and motility. J Biol Chem. 2004;279:48443–8.PubMedCrossRef

17.

Woolhiser MR, Brockow K, Metcalfe DD. Activation of human mast cells by aggregated IgG through FcγRI: additive effects of C3a. Clin Immunol. 2004;110:172–80.PubMedCrossRef

18.

Venkatesha RT, Berla TE, Zaidi AK, Ali H. Distinct regulation of C3a-induced MCP-1/CCL2 and RANTES/CCL5 production in human mast cells by extracellular signal regulated kinase and PI3 kinase. Mol Immunol. 2005;42:581–7.PubMedCrossRef

19.

Jolly PS, Bektas M, Olivera A, Gonzalez-Espinosa C, Proia RL, Rivera J, et al. Transactivation of sphingosine-1-phosphate receptors by FcεRI triggering is required for normal mast cell degranulation and chemotaxis. J Exp Med. 2004;199:959–70.PubMedCrossRef

20.

Wang XS, Lau HY. Prostaglandin E potentiates the immunologically stimulated histamine release from human peripheral blood-derived mast cells through EP1/EP3 receptors. Allergy. 2006;61:503–6.PubMedCrossRef

21.

Kulka M, Alexopoulou L, Flavell RA, Metcalfe DD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol. 2004;114:174–82.PubMedCrossRef

22.

Bischoff SC, Dahinden CA. c-kit ligand: a unique potentiator of mediator release by human lung mast cells. J Exp Med. 1992;175:237–44.PubMedCrossRef

23.

Iemura A, Tsai M, Ando A, Wershil BK, Galli SJ. The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis. Am J Pathol. 1994;144:321–8.PubMed

24.

Yee NS, Paek I, Besmer P. Role of kit-ligand in proliferation and suppression of apoptosis in mast cells: basis for radiosensitivity of white spotting and steel mutant mice. J Exp Med. 1994;179:1777–87.PubMedCrossRef

25.

Mekori YA, Oh CK, Metcalfe DD. The role of c-Kit and its ligand, stem cell factor, in mast cell apoptosis. Int Arch Allergy Immunol. 1995;107:136–8.PubMed

26.

Metcalfe DD, Mekori JA, Rottem M. Mast cell ontogeny and apoptosis. Exp Dermatol. 1995;4:227–30.PubMedCrossRef

27.

Lukacs NW, Kunkel SL, Strieter RM, Evanoff HL, Kunkel RG, Key ML, et al. The role of stem cell factor (c-kit ligand) and inflammatory cytokines in pulmonary mast cell activation. Blood. 1996;87:2262–8.PubMed

28.

Lin TJ, Befus AD. Differential regulation of mast cell function by IL–10 and stem cell factor. J Immunol. 1997;159:4015–23.PubMed

29.

Gagari E, Tsai M, Lantz CS, Fox LG, Galli SJ. Differential release of mast cell interleukin-6 via c-kit. Blood. 1997;89:2654–63.PubMed

30.

Tkaczyk C, Beaven MA, Brachman SM, Metcalfe DD, Gilfillan AM. The phospholipase C gamma 1-dependent pathway of FcεRI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. J Biol Chem. 2003;278:48474–84.PubMedCrossRef

31.

Tkaczyk C, Metcalfe DD, Gilfillan AM. Determination of protein phosphorylation in FcεRI-activated human mast cells by immunoblot analysis requires protein extraction under denaturing conditions. J Immunol Methods. 2002;268:239–43.PubMedCrossRef

32.

Iwaki S, Jensen BM, Gilfillan AM. Ntal/Lab/Lat2. Int J Biochem Cell Biol. 2007;39:868–73.PubMedCrossRef

33.

Iwaki S, Spicka J, Tkaczyk C, Jensen BM, Furumoto Y, Charles N, et al. Kit- and FcεRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells. Cell Signal. 2008;20:195–205.PubMedCrossRef

34.

Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, et al. Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature. 2004;431:1007–11.PubMedCrossRef

35.

Fluckiger AC, Li Z, Kato RM, Wahl MI, Ochs HD, Longnecker R, et al. Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation. EMBO J. 1998;17:1973–85.PubMedCrossRef

36.

Saitoh S, Arudchandran R, Manetz TS, Zhang W, Sommers CL, Love PE, et al. LAT is essential for FcεRI-mediated mast cell activation. Immunity. 2000;12:525–35.PubMedCrossRef

37.

Parravicini V, Gadina M, Kovarova M, Odom S, Gonzalez-Espinosa C, Furumoto Y, et al. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nat Immunol. 2002;3:741–8.PubMed

38.

Dann SG, Selvaraj A, Thomas G. mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med. 2007;13:252–9.PubMedCrossRef

39.

Kim MS, Kuehn HS, Metcalfe DD, Gilfillan AM. Activation and function of the mTORC1 pathway in mast cells. J Immunol. 2008;180:4586–95.PubMed

40.

Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007;110:2331–3.PubMedCrossRef

41.

Jensen BM, Metcalfe DD, Gilfillan AM. Targeting kit activation: a potential therapeutic approach in the treatment of allergic inflammation. Inflamm Allergy Drug Targets. 2007;6:57–62.PubMedCrossRef

42.

Jensen BM, Akin C, Gilfillan AM. Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders. Br J Pharmacol. 2008;154:1572–82.PubMedCrossRef

43.

Jensen BM, Beaven MA, Iwaki S, Metcalfe DD, Gilfillan AM. Concurrent inhibition of kit- and FcεRI-mediated signaling: coordinated suppression of mast cell activation. J Pharmacol Exp Ther. 2008;324:128–38.PubMedCrossRef

Title: Amplification mechanisms for the enhancement of antigen-mediated mast cell activation
Authors: Alasdair M. Gilfillan
Richard D. Peavy
Dean D. Metcalfe
Publication date: 01-03-2009
Publisher: Humana Press Inc
Published in: Immunologic Research / Issue 1-3/2009
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI: https://doi.org/10.1007/s12026-008-8046-9

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Amplification mechanisms for the enhancement of antigen-mediated mast cell activation

Abstract

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Abstract

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