Monomeric IgE Stimulates Signaling Pathways in Mast Cells that Lead to Cytokine Production and Cell Survival

Kalesnikoff, Janet; Huber, Michael; Lam, Vivian; Damen, Jacqueline E.; Zhang, Juan; Siraganian, Reuben P.; Krystal, Gerald

doi:10.1016/s1074-7613(01)00159-5

Cited by 363 publications

(420 citation statements)

References 48 publications

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“…A current operating hypothesis is that certain IgE Abs may be capable of self-aggregating once engaged in Fc⑀RI. This self-aggregation appears to require an empty ligand binding site because monovalent ligand can markedly blunt the signals induced by the presence of the putatively monomeric IgE (29). Although the current evidence suggests that this effect may be restricted to certain IgE Abs, it remains a concern for a clear interpretation of our results.…”

Section: Discussionmentioning

confidence: 67%

“…As noted previously, a recent study using cultured mouse mast cells indicated that monomeric IgE could induce a large number of the signaling steps formerly associated with aggregating stimuli (29). Notably, although these signaling elements are active, these apparently activated mast cells do not degranulate or secrete arachidonic acid metabolites.…”

Section: Discussionmentioning

confidence: 74%

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Two Regions of Down-Regulation in the IgE-Mediated Signaling Pathway in Human Basophils

MacGlashan¹

2003

The Journal of Immunology

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Previous studies demonstrated that after stimulation of human basophils with a polyclonal anti-IgE Ab, early signaling elements showed sustained phosphorylation, whereas later elements were transient, suggesting that a region of down-regulation involved inhibition of phosphatidylinositol (PI) 3 kinase or its products. However, the current studies show that under some conditions, syk phosphorylation is transient. Generally, stimulation with a variety of Ags makes this early form of down-regulation more apparent. An exploration of the conditions needed to induce early down-regulation indicates that both the nature of aggregation and the cell surface density of IgE play roles. It was also found that the previously described late form of down-regulation (PI3 kinase product transience) can occur in cells displaying early down-regulation (transient syk phosphorylation), but this phenomenon is revealed by testing for subsequent down-regulation of the response to non-cross-reacting stimuli, altering their ability to induce phosphorylation of Akt or extracellular signal-regulated kinase. In contrast, phosphorylation of syk kinase, in response to a non-cross-reacting stimulus, was relatively unaffected by prior stimulation. The magnitude of cross-desensitization of the Akt or extracellular signal-regulated kinase response was a function of the strength of the first stimulus. Mediator release showed a similar cross-desensitization effect. Therefore, stimulation induces two forms of down-regulation, one operating before or at the level of syk phosphorylation, possibly characterizing the process formerly known as specific desensitization, and one that operates in the region of PI3 kinase, accounting for the process formerly known as nonspecific desensitization, which is dependent on the strength of stimulus.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 74%

Two Regions of Down-Regulation in the IgE-Mediated Signaling Pathway in Human Basophils

MacGlashan¹

2003

The Journal of Immunology

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“…An exposure of mast cells to IgE in the absence of antigen was indeed reported 1) to up-regulate the expression of membrane FcεRI (Hsu and MacGlashan, 1996;MacGlashan et al, 1997), 2) to increase the survival of mast cells in the absence of growth factors (Asai et al, 2001;Kawakami and Galli, 2002), and 3) to induce cytokine secretion (Kalesnikoff et al, 2001;Pandey et al, 2004;Kohno et al, 2005). The effect of monomeric IgE on mast cell survival and cytokine secretion was found to depend on the FcRγ ITAM (Kohno et al, 2005), but not the up-regulation of FcεRI expression.…”

Section: Ligand Valency Influence Fcεri-dependent Mast Cell Secretorymentioning

confidence: 90%

“…Supporting the conclusion that BMMC from SHIP1 -/-mice could respond to a lower degree of receptor aggregation, IgE anti-DNP alone could trigger these cells, but not wt-type cells, to release β-hexosaminidase, as well as an array of cytokines. These antigen-independent responses were inhibited by a monovalent hapten such as DNP-lysine (Huber et al, 1998;Kalesnikoff et al, 2001). IgEinduced increased degranulation was correlated with augmented and sustained Ca 2+ mobilization and Erk1/2 activation.…”

Section: Inositol Phosphatasesmentioning

confidence: 95%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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“…Recently, however, IgE was reported to increase the survival of mouse mast cells in the absence of IL-3 [13,14] and to induce FcεRI internalization, cytokine secretion and degranulation [15,16]. These responses were all induced by high concentrations (several µg/ml) of monoclonal IgE anti-DNP/TNP, among which highly and poorly "cytokinergic" IgE were distinguished [17].…”

Section: Monomeric Ige and Fcεri Signalingmentioning

confidence: 99%

Regulation of allergy by Fc receptors

Bruhns

Frémont

Daëron

2005

Current Opinion in Immunology

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SummaryThe aggregation of high-affinity IgE receptors (FcεRI) on mast cells and basophils has long been known to be the critical event that initiates allergic reactions. Monomeric IgE was recently found to induce a variety of effects when binding to FcεRI. Up-regulation of FcεRI required binding only, whereas other responses resulted from FcεRI aggregation. Interestingly, FcεRI aggregation has been understood to generate a mixture of positive and negative intracellular signals. Mast cells/basophils express also low-affinity and, under specific conditions, high-affinity IgG receptors. When co-engaging these receptors with FcεRI, IgG antibodies can amplify or dampen IgE-induced mast cell activation. Based on these findings, FcRs have been proposed to be used as targets and/or tools for new therapeutic approaches of allergies.

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Monomeric IgE Stimulates Signaling Pathways in Mast Cells that Lead to Cytokine Production and Cell Survival

Cited by 363 publications

References 48 publications

Two Regions of Down-Regulation in the IgE-Mediated Signaling Pathway in Human Basophils

Two Regions of Down-Regulation in the IgE-Mediated Signaling Pathway in Human Basophils

Negative Signaling in Fc Receptor Complexes

Regulation of allergy by Fc receptors

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