Blockade of Inflammation and Airway Hyperresponsiveness in Immune-sensitized Mice by Dominant-Negative Phosphoinositide 3-Kinase–TAT

Myou, Shigeharu; Leff, Alan R.; Myo, Saori; Boetticher, Evan; Tong, Jiankun; Meliton, Angelo Y.; Liu, Jie; Muñoz, N. M.; Zhu, Xiangdong

doi:10.1084/jem.20030298

Cited by 230 publications

(193 citation statements)

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“…[10][11][12] Several lines of evidence have suggested that SHIP-1, as a regulator of the PI3K pathway, might have a role in allergic response. In vitro studies have shown that SHIP-1 functioned as a negative regulator in mast cell degranulation in mouse cells 19 and human cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, several recent studies have suggested that the PI3K pathway might also be involved in the T H 2 inflammatory response in mouse models of allergic asthma. 10,11 Either PI3K inhibitors 10 or expression of a dominant-negative PI3K subunit reduced the inflammatory response of the airway to antigen challenge. 11 The intracellular level of PIP3 is a critical point for regulation.…”

mentioning

confidence: 99%

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Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Zheng

Bailey

et al. 2007

Journal of Allergy and Clinical Immunology

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Background-Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the T H 2 activation pathway has not been established. SHIP-1 −/− mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Zheng

Bailey

et al. 2007

Journal of Allergy and Clinical Immunology

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“…Since IL-5 is a key cytokine responsible for eosinophil differentiation and survival [1,11], we determined in subsequent studies IL-5 levels in the BALF of c-maf-Tg and control mice. .…”

Section: Spontaneously Increased Eosinophilia Andmentioning

confidence: 99%

“…Increased numbers of CD4 + T cells expressing IL-4 and IL-5 have been found in the airways of asthmatic subjects [2]. Whereas IL-4 plays a central role in immunoglobulin E (IgE)-mediated responses, IL-5 is crucial for eosinophil recruitment and activation, which is observed during the late asthmatic reaction [3,9,11]. Th2 cells develop from naive T cells under the influence of IL-4 produced by Tand non-T cells such as IgE-activated mast cells [4,9].…”

Section: Introductionmentioning

confidence: 99%

A stage‐specific functional role of the leucine zipper transcription factor c‐Maf in lung Th2 cell differentiation

Hausding¹,

Lehr³

et al. 2004

Eur J Immunol

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The transcription factor c-Maf controls IL-4 gene expression in CD4 + T cells, and its expression is up-regulated in human asthmatic airways after allergen challenge. In the present study, we addressed the role of c-Maf in asthma by studying transgenic (Tg) mice overexpressing c-Maf in CD4 + T cells under the control of the CD2 promoter. As shown, lung CD4 + T cells of c-maf-Tg mice produced more IL-5 at the early stage (day 2) of culture in the presence of IL-4 than wild-type control cells. Consistently, c-maf-Tg mice spontaneously showed increased IL-5 expression and eosinophils in the bronchial alveolar lavage fluid (BALF) and activated IL-5 signal transduction via Raf-1 and Ras in lung eosinophils. Finally, IL-13 was suppressed in the BALF of c-maf-Tg mice and in supernatants of Tg lung CD4 + T cells cultured in the presence of IL-2. Consistently, retroviral overexpression of c-Maf suppressed IL-13 production in developing lung Th2 cells. In summary, c-Maf induces IL-5 production in lung CD4 + T cells at an early stage, but along with IL-2 suppresses IL-13 production in differentiating lung Th2 cells, thereby explaining the finding that overexpression of c-Maf does not cause airway hyperresponsiveness, a hallmark feature of asthma.

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“…In contrast, p110d-deficient B cells have major defects in activation by multiple stimuli in vitro, and blunted antibody responses in vivo [11][12][13]. Thus, while PI3K isoforms likely play distinct roles in B cells, T cells and neutrophils, their respective roles in regulating systemic cytokine production patterns, cell-mediated immunity and host defense functions remain unexplored.Several studies have shown that global inhibition of PI3K signaling using small-molecule inhibitors [14,15], antagonistic phosphatases [16] or cell-permeable antagonistic proteins [17] leads to a reduction of Th2-dependent airway inflammation in mouse models of allergic asthma. While these results implicate PI3K in asthma pathogenesis at some level, the cellular and molecular mechanisms are poorly understood, and the PI3K isoforms involved remain to be identified.…”

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confidence: 99%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

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Phosphoinositide 3-kinases (PI3K) regulate immune activation via their roles in signal transduction of multiple classes of receptors. Here, we examined the effect of genetic inactivation of the hemopoietic cell-restricted PI3K isoform p110d on systemic cytokine and chemokine responses and allergic airway inflammation. We found that type 2 cytokine responses (IL-4, IL-5 and IL-13) are significantly decreased in p110d mutants, whereas type 1 cytokine responses (IFN-c and CXCL10) were robust. Elevated IFN-c production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-c and IL-10 production normalized after secondary OVA immunization; however, type 2 cytokine production was persistently reduced. Type 2 cytokine-dependent airway inflammation elicited by intranasal challenge with OVA was dramatically reduced, with reduced levels of eosinophil recruitment and mucus production observed in the lungs. Induction of respiratory hyper-responsiveness to inhaled methacholine, a hallmark of asthma, was markedly attenuated in p110d-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110d-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110d signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease. IntroductionPhosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating immune function [1,2]. PI3K are activated by stimulation through a variety of receptor types, including antigen receptors, costimulatory receptors and certain cytokine receptors. PI3K function by phosphorylating specific plasma membrane phospholipids to generate short-lived, membrane-integral lipid [3,4]. Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.Recent work has begun to explore the specific roles of different PI3K catalytic subunit isoforms in immune function. Analysis of p110a and p110b deficiency has been hindered by the lethality of these mutations [8,9]. Mice deficient in the class IB subunit p110c are viable and have defects in T cell development and activation, as well as severe defects in neutrophil function, while B cell activation appears normal [1...

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Blockade of Inflammation and Airway Hyperresponsiveness in Immune-sensitized Mice by Dominant-Negative Phosphoinositide 3-Kinase–TAT

Cited by 230 publications

References 53 publications

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

A stage‐specific functional role of the leucine zipper transcription factor c‐Maf in lung Th2 cell differentiation

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

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