IL-4 and -5 prime human mast cells for different profiles of IgE-dependent cytokine production

Ochi, Hiroshi; Jesus, Nidia H. De; Hsieh, Fred H.; Austen, K. Frank; Boyce, Joshua A.

doi:10.1073/pnas.180318697

Cited by 106 publications

(72 citation statements)

References 63 publications

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“…In agreement with previous results, 25 hMCs generated and maintained in SCF secrete only minute amounts of TNF-␣ in response to Fc⑀RI cross-linking (data not shown). In contrast, passive sensitization and challenge of hMCs with Ag induced a significant amount of CCL2 secretion ( Figure 5B).…”

Section: S1p Is a Strong Inducer Of Hmc Degranulation And Secretion Osupporting

confidence: 93%

Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

Oskeritzian

Alvarez

Hait

et al. 2008

Blood

114

127

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Sphingosine-1-phosphate (S1P) is now emerging as a potent lipid mediator produced by mast cells that contributes to inflammatory and allergic responses. In contrast to its weak effect on degranulation of murine mast cells, S1P potently induced degranulation of the human LAD2 mast-cell line and cord blood-derived human mast cells (hMCs). S1P also stimulated production and secretion of cytokines, TNF-␣ and IL-6, and markedly enhanced secretion of a chemokine, CCL2/MCP-1, important modulators of inflammation. S1P is produced in mast cells by the 2 sphingosine kinases, SphK1 and SphK2. SphK1 but not SphK2 plays a critical role in IgE/Ag-induced degranulation, migration toward antigen, and CCL2 secretion from hMCs, as determined by specifically down-regulating their expression. However, both isoenzymes were required for efficient TNF-␣ secretion. Taken together, our data suggest that differential formation of S1P by SphK1 and SphK2 has distinct and important actions in hMCs. IntroductionMast cells (MCs) play pivotal roles in immediate-type and inflammatory allergic reactions initiated by cross-linking with antigen (Ag) of the antigen-specific immunoglobulin E (IgE) on their cell-surface high-affinity receptors for IgE (Fc⑀RI). MC activation leads to release of preformed mediators, such as histamine, localized in specialized granules, and the de novo synthesis and secretion of a plethora of cytokines, chemokines, eicosanoids, and the bioactive sphingolipid metabolite, sphingosine-1-phosphate (S1P). The combined actions of these mediators trigger symptoms associated with allergy and propagate inflammatory responses. S1P levels are elevated in the bronchoalveolar lavage (BAL) fluid of asthmatics after Ag challenge, suggesting that secretion of S1P by MCs is of relevance in inflammatory responses and asthma. 1 S1P is a ligand for 5 G protein-coupled receptors (GPCRs), designated S1P 1-5 , through which it exerts many of its actions. 2,3 Indeed, S1P is secreted by activated MCs, 4,5 and studies with rodent MCs have shown that this S1P is able to rapidly bind and activate its receptors, S1P 1 and S1P 2 , in an autocrine manner. S1P 1 induces cytoskeletal rearrangements, leading to the movement of MCs toward an Ag gradient, whereas activation of S1P 2 is critical for degranulation. 4 In rodent MCs and human bone marrow-derived mast cells (BMMCs), aggregation of Fc⑀RI leads to activation of both isoforms of sphingosine kinase, SphK1 and SphK2, the enzymes that produce S1P from sphingosine. 4,6-8 Down-regulation of SphK1 but not SphK2 in these MCs inhibits calcium mobilization, degranulation, and migration induced by Ag. 4,6,7 In human BMMCs and murine MCs, SphK1 translocates to the plasma membrane within minutes of Fc⑀RI clustering. 4,6 SphK1 interacts with the protein tyrosine kinases, Src kinase members Lyn and Fyn (Fc⑀RI proximal kinases that initiate the signaling events following cross-linking of this receptor), but not Src or other tyrosine kinases, such as Syk. Following interaction with Lyn, SphK1 is recruited to me...

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Section: S1p Is a Strong Inducer Of Hmc Degranulation And Secretion Osupporting

confidence: 93%

Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

Oskeritzian

Alvarez

Hait

et al. 2008

Blood

114

127

View full text Add to dashboard Cite

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“…During the last years IL-4 has been recognized as an important regulator of human mast cells derived from intestine, lung, skin, or cord blood (5)(6)(7)(8)(9)(10)(11). In synergy with SCF, IL-4 enhances proliferation, mediator release, and Th2 cytokine generation.…”

Section: Discussionmentioning

confidence: 99%

IL-4-Induced Priming of Human Intestinal Mast Cells for Enhanced Survival and Th2 Cytokine Generation Is Reversible and Associated with Increased Activity of ERK1/2 and c-Fos

Lorentz

Wilke

Sellge

et al. 2005

The Journal of Immunology

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In synergy with stem cell factor (SCF), IL-4 strongly enhances mast cell proliferation and shifts IgE-dependent cytokine production in mature human mast cells toward an increased release of Th2 cytokines such as IL-3, IL-5, and IL-13 and a decreased IL-6 expression. In this study we analyzed the kinetics and the mechanisms of these IL-4 effects on mast cells purified from intestinal tissue. If the cells were first cultured with IL-4 for 14 days and then without IL-4 for another 14 days, mast cells lost the capacity of producing higher amounts of Th2 cytokines and regained the capacity of producing IL-6. The IL-4-induced up-regulation of mast cell proliferation and FcεRI expression was also reversible if IL-4 was withdrawn for 14 days. Interestingly, in contrast to IL-4, proliferation and phenotype of human intestinal mast cells were not affected by IL-13 although both cytokines were capable of inducing STAT6 activation. Instead, IL-4 treatment (but not IL-13 treatment) was associated with an increased activity of ERK1/2 and c-Fos, the downstream target of ERK1/2 and component of the transcription factor AP-1. Consistently, mast cell proliferation and cytokine expression in response to IL-4 was blocked by the MEK inhibitor PD98059. In summary, our data show that the IL-4 effects on human intestinal mast cell functions are reversible and accompanied by an increased activity of ERK1/2 and c-Fos.

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“…Cells were harvested for studies when Ͼ95% stained metachromatically with toluidine blue dye (typically 6 -9 wk). To optimize conditions for Fc⑀RI-dependent exocytosis, cytokine generation, and eicosanoid production, hMCs were transferred to new medium containing SCF and IL-4 (10 ng/ml; R&D Systems) for 5 days at 37°C and 5% CO 2 before activation (32,33).…”

Section: Derivation Of Hmcsmentioning

confidence: 99%

“…For measurements of cytokine generation, triplicate samples of 1 ϫ 10 5 passively sensitized, primed hMCs were challenged with PGN (10 g/ml; Sigma-Aldrich), anti-IgE (1 g/ml), LTD 4 (100 nM; Cayman), or medium alone in the presence or the absence of ADP, ATP, ATP␥S, BzATP, or adenosine at various concentrations in the wells of 96-well, flat-bottom plates. The agonist doses were optimal for cytokine generation by IL-4-primed hMCs and were chosen on the basis of preliminary dose-response experiments as well as previously published data (32,37). In some experiments the cells were pretreated for 30 min with H89 (10 M; Sigma-Aldrich), a selective inhibitor of protein kinase A (PKA).…”

Section: Cell Activation For Secretionmentioning

confidence: 99%

Adenine Nucleotides Inhibit Cytokine Generation by Human Mast Cells through a Gs-Coupled Receptor

Cheng

Mery

Beller

et al. 2004

The Journal of Immunology

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ATP and ADP activate functionally distinct G protein-coupled purinergic (P2Y) receptors. We determined the expression and function of adenine nucleotide-specific P2Y receptors on cord blood-derived human mast cells (hMCs). Human MCs expressed mRNA encoding the ADP-specific P2Y1, P2Y12, and P2Y13 receptors; the ATP/UTP-specific P2Y2 receptor; and the ATP-selective P2Y11 receptor. ADP (0.05–50 μM) induced calcium flux that was completely blocked by a P2Y1 receptor-selective antagonist and was not cross-desensitized by ATP. Low doses of ADP induced strong phosphorylation of ERK and p38 MAPKs; higher doses stimulated eicosanoid production and exocytosis. Although MAPK phosphorylation was blocked by a combination of P2Y1- and P2Y12-selective antagonists, neither interfered with secretion responses. Unexpectedly, both ADP and ATP inhibited the generation of TNF-α in response to the TLR2 ligand, peptidoglycan, and blocked the production of TNF-α, IL-8, and MIP-1β in response to leukotriene D4. These effects were mimicked by two ATP analogues, adenosine 5′-O-(3-thiotriphosphate) and 2′,3′-O-(4-benzoyl-benzoyl) adenosine 5′-triphosphate (BzATP), but not by adenosine. ADP, ATP, adenosine 5′-O-(3-thiotriphosphate), and 2′,3′-O-(4-benzoyl-benzoyl) adenosine 5′-triphosphate each induced cAMP accumulation, stimulated the phosphorylation of CREB, and up-regulated the expression of inducible cAMP early repressor, a CREB-dependent inhibitor of cytokine transcription. Human MCs thus express several ADP-selective P2Y receptors and at least one Gs-coupled ADP/ATP receptor. Nucleotides could therefore contribute to MC-dependent microvascular leakage in atherosclerosis, tissue injury, and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs.

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IL-4 and -5 prime human mast cells for different profiles of IgE-dependent cytokine production

Cited by 106 publications

References 63 publications

Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

IL-4-Induced Priming of Human Intestinal Mast Cells for Enhanced Survival and Th2 Cytokine Generation Is Reversible and Associated with Increased Activity of ERK1/2 and c-Fos

Adenine Nucleotides Inhibit Cytokine Generation by Human Mast Cells through a Gs-Coupled Receptor

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