Increased Expression of Genes Linked to FcεRI Signaling and to Cytokine and Chemokine Production in Lyn-Deficient Mast Cells

Hernandez-Hansen, Valerie; Bard, Julie D. J.; Tarleton, Christy A.; Wilder, Julie A.; Lowell, Clifford A.; Wilson, Bridget S.; Oliver, Janet M.

doi:10.4049/jimmunol.175.12.7880

Cited by 24 publications

(24 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytokine production in mast cells as a consequence of Fc RI stimulation seems to be primarily driven by Fyn and not Lyn kinase (23,24). In fact, Fc RI-dependent stimulation of IL-4 production was demonstrated to be defective in Fyn-deficient BMMC but not in Lyn deficiency (23)(24)(25) To determine whether Lyn and/or Fyn might be required for H 2 O 2 -induced IL-4 production, we analyzed IL-4 mRNA up-regulation using BMMC from Lyn Ϫ/Ϫ , Fyn Ϫ/Ϫ , and PI3K Ϫ/Ϫ mice.…”

Section: H 2 O 2 -Induced Il-4 Up-regulation Requires Fynmentioning

confidence: 99%

“…In fact, Fc RI-dependent stimulation of IL-4 production was demonstrated to be defective in Fyn-deficient BMMC but not in Lyn deficiency (23)(24)(25) To determine whether Lyn and/or Fyn might be required for H 2 O 2 -induced IL-4 production, we analyzed IL-4 mRNA up-regulation using BMMC from Lyn Ϫ/Ϫ , Fyn Ϫ/Ϫ , and PI3K Ϫ/Ϫ mice. BMMC from wild type, Lyn-, Fyn-, and PI3K-null mice were treated with 10 nM H 2 O 2 for 3 h and then analyzed together with untreated samples for IL-4 mRNA production.…”

Section: H 2 O 2 -Induced Il-4 Up-regulation Requires Fynmentioning

confidence: 99%

See 1 more Smart Citation

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

Frossi

Rivera

Hirsch

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Mast cells have the ability to react to multiple stimuli, implicating these cells in many immune responses. Specific signals from the microenvironment in which mast cells reside can activate different molecular events that govern distinct mast cells responses. We previously demonstrated that hydrogen peroxide (H2O2) promotes IL-4 and IL-6 mRNA production and potentates FcεRI-induced cytokine release in rat basophilic leukemia RBL-2H3 cells. To further evaluate the effect of an oxidative microenvironment (which is physiologically present in an inflammatory site) on mast cell function and the molecular events responsible for mast cell cytokine production in this environment, we analyzed the effect of H2O2 treatment on IL-4 production in bone marrow-derived, cultured mast cells. Our findings show that nanomolar concentrations of H2O2 induce cytokine secretion and enhance IL-4 production upon FcεRI triggering. Oxidative stimulation activates a distinct signal transduction pathway that induces Fyn/PI3K/Akt activation and the selective phosphorylation of p38 MAP kinase. Moreover, H2O2 induces AP-1 and NFAT complexes that recognize the IL-4 promoter. The absence of Fyn and PI3K or the inhibition of p38 MAPK activity demonstrated that they are essential for H2O2-driven IL-4 production. These findings show that mast cells can respond to an oxidative microenvironment by initiating specific signals capable of eliciting a selective response. The findings also demonstrate the dominance of the Fyn/p38 MAPK pathway in driving IL-4 production.

show abstract

Section: H 2 O 2 -Induced Il-4 Up-regulation Requires Fynmentioning

confidence: 99%

Section: H 2 O 2 -Induced Il-4 Up-regulation Requires Fynmentioning

confidence: 99%

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

Frossi

Rivera

Hirsch

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Polymerase chain reaction (PCR) and microarray analysis of various sources of MC RNA for R4 RGS family members revealed expression of Rgs1, 8,13,16 13 and 18 (data not shown). We focused on Rgs13 because microarray studies of purified human cell subsets showed restricted RGS13 expression in MCs compared to other hematopoietic cells (Fig.…”

Section: Enrichment Of Rgs13 In Mcsmentioning

confidence: 99%

“…RGS isoforms can be further divided into subfamilies on the basis of additional protein interaction motifs. However, the R4 subfamily of 8,13,16,18,and 21) …”

Section: Introductionmentioning

confidence: 99%

“…RGS isoforms can be further divided into subfamilies on the basis of additional protein interaction motifs. However, the R4 subfamily of RGSs (RGS1-5, 8,13,16,18, and 21) contains only short peptide sequences flanking the RGS domain. Despite extensive characterization of their biochemical actions in vitro, the physiological function of most R4 RGS proteins remains unknown.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Suppression of immunoglobulin E–mediated allergic responses by regulator of G protein signaling 13

et al. 2007

View full text Add to dashboard Cite

Mast cells provoke allergic responses through degranulation and release of proinflammatory mediators after antigen crosslinking of the high affinity immunoglobulin E (IgE) receptor (FcεRI). Regulator of G protein Signaling (RGS) proteins negatively control G-protein-coupled receptormediated signaling through GTPase accelerating protein (GAP) activity. Here, we show that Rgs13 inhibits allergic responses by physically interacting with the regulatory p85α subunit of PI3K in mast cells and disrupting its association with an FcεRI-activated scaffold complex. Rgs13 −/− mice exhibited increased IgE-mediated mast cell degranulation and anaphylaxis. Thus, apart from its regulation of GPCRs, Rgs13 inhibits immune receptor-induced signalosome assembly in MCs. Abnormal Rgs13 expression or function may underlie some cases of idiopathic anaphylaxis or disorders of amplified MC activity.MCs lie in close proximity to nerves and blood vessels in organs exposed to constant environmental challenge such as skin and respiratory and gastrointestinal tract mucosae, suggesting a sentinel function in the innate immune response 1 . MCs also provoke allergic diseases such as asthma and anaphylaxis accompanied by high levels of Ag-specific IgE. In allergic individuals, Ag crosslinks IgE bound to FcεRI on MCs, eliciting release of proinflammatory compounds such as histamine and synthesis of leukotrienes and cytokines. Collectively, these mediators initiate type I hypersensitivity reactions characterized by increased vascular permeability, edema, and smooth muscle contraction.FcεRI is a multiunit immune recognition receptor consisting of α, β, and two γ chains. The α subunit binds IgE while the β and γ subunits transduce extracellular signals 2 . FcεRI crosslinking by IgE/Ag induces phosphorylation of immunoreceptor-based tyrosine activation motifs (ITAMs) in the intracellular portion of the β and γ chains by Lyn tyrosine kinase, which attracts Syk kinase to the γ chain. Tyrosine phosphorylation of Syk then propagates the signaling pathway by recruitment and activation of PI(3)K, phospholipase Cγ (PLCγ), and mitogen-activated protein kinase (MAPK). PI(3)K has an essential function in MC homeostasis and allergic responses 3 . Deletion of p110δ, the principal catalytic PI(3)K subunit in BMMCs, significantly impairs Ag-induced degranulation 4 . PI(3)K-mediated activation of PLCγ, which catalyzes formation of inositol-1, 4, 5 trisphosphate (IP3), evokes a rise in intracellular Ca ++ concentration leading to degranulation 5 . to FcεRI, GPCRs catalyze GDP-GTP exchange on the α subunit of a heterotrimeric G protein to activate a variety of effector pathways 10 . Signaling terminates through the intrinsic GTPase activity of the α subunit, which results in conversion of Gα-GTP to Gα-GDP. Gα-GDP binds Gβγ with high affinity, re-constituting the inactive heterotrimer.RGS proteins specify GPCR signaling durability and intensity through GTPase accelerating (GAP) activity on Gα subunits and/or antagonism of Gα-effector interactions, which results...

show abstract

RGS-Insensitive Gα Subunits: Probes of Gα Subtype-Selective Signaling and Physiological Functions of RGS Proteins

Kaur

Kehrl

Charbeneau

et al. 2011

Methods in Molecular Biology

View full text Add to dashboard Cite

The Regulator of G protein Signaling (RGS) proteins were identified as a family in 1996 and humans have more than 30 such proteins. Their best known function is to suppress G Protein-Coupled Receptors (GPCR) signaling by increasing the rate of Gα turnoff through stimulation of GTPase activity (i.e., GTPase acceleration protein or GAP activity). The GAP activity of RGS proteins on the Gαi and Gαq family of G proteins can terminate signals initiated by both α and βγ subunits. RGS proteins also serve as scaffolds, assembling signal-regulating modules. Understanding the physiological roles of RGS proteins is of great importance, as GPCRs are major targets for drug development. The traditional method of using RGS knockout mice has provided some information about the role of RGS proteins but in many cases effects are modest, perhaps because of redundancy in RGS protein function. As an alternative approach, we have utilized a glycine-to-serine mutation in the switch 1 region of Gα subunits that prevents RGS binding. The mutation has no known effects on Gα binding to receptor, Gβγ, or effectors. Alterations in function resulting from the G>S mutation imply a role for both the specific mutated Gα subunit and its regulation by RGS protein activity. Mutant rodents expressing these G>S mutant Gα subunits have strong phenotypes and provide important information about specific physiological functions of Gαi2 and Gαo and their control by RGS. The conceptual framework behind this approach and a summary of recent results is presented in this chapter.

show abstract

Increased Expression of Genes Linked to FcεRI Signaling and to Cytokine and Chemokine Production in Lyn-Deficient Mast Cells

Cited by 24 publications

References 47 publications

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

Suppression of immunoglobulin E–mediated allergic responses by regulator of G protein signaling 13

RGS-Insensitive Gα Subunits: Probes of Gα Subtype-Selective Signaling and Physiological Functions of RGS Proteins

Contact Info

Product

Resources

About