Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110 but Not p110 Promotes Optimal Allergic Responses In Vivo (original) (raw)
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European Journal of Immunology, 2007
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 p110δ 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 p110δ mutants, whereas type 1 cytokine responses (IFN-γ and CXCL10) were robust. Elevated IFN-γ production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-γ 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 p110δ-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110δ-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110δ signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease.
The FASEB Journal, 2006
P110␦ phosphoinositide 3-kinase (PI3K) plays a pivotal role in the recruitment and activation of certain inflammatory cells. Recent findings revealed that the activity of p110␦ also contributes to allergen-IgE-induced mast cell activation and vascular permeability. We investigated the role of p110␦ in allergic airway inflammation and hyperresponsiveness using IC87114, a selective p110␦ inhibitor, in a mouse asthma model. BALB/c mice were sensitized with OVA and, upon OVA aerosol challenge, developed airway eosinophilia, mucus hypersecretion, elevation in cytokine and chemokine levels, up-regulation of ICAM-1 and VCAM-1 expression, and airway hyperresponsiveness. Intratracheal administration of IC87114 significantly (P<0.05) attenuated OVA-induced influx into lungs of total leukocytes, eosinophils, neutrophils, and lymphocytes, as well as levels of IL-4, IL-5, IL-13, and RANTES in a dose-dependent manner. IC87114 also significantly (P<0.05) reduced the serum levels of total IgE and OVA-specific IgE and LTC 4 release into the airspace. Histological studies show that IC87114 inhibited OVAinduced lung tissue eosinophilia, airway mucus production, and inflammation score. In addition, IC87114 significantly (P<0.05) suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. Western blot analyses of whole lung tissue lysates shows that IC87114 markedly attenuated the OVA-induced increase in expression of IL-4, IL-5, IL-13, ICAM-1, VCAM-1, RANTES, and eotaxin. Furthermore, IC87114 treatment markedly attenuated OVA-induced serine phosphorylation of Akt, a downstream effector of PI3K signaling. Taken together, our findings implicate that inhibition of p110␦ signaling pathway may have therapeutic potential for the treatment of allergic airway inflammation.-Lee, K. S., Lee, H. K., Hayflick, J. S., Lee, Y. C., Puri, K. D. Inhibition of phosphoinositide 3-kinase ␦ attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J.
Targeting phosphoinositide 3-kinase δ for allergic asthma
Biochemical Society Transactions, 2012
Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kδ (phosphoinositide 3-kinase δ) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlle...
Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I
Journal of Experimental Medicine, 2005
The membrane phospholipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P 2 ] is a critical signal transducer in eukaryotic cells. However, the physiological roles of the type I phosphatidylinositol phosphate kinases (PIPKIs) that synthesize PI(4,5)P 2 are largely unknown. Here, we show that the ␣ isozyme of PIPKI (PIPKI ␣ ) negatively regulates mast cell functions and anaphylactic responses. In vitro, PIPKI ␣ -deficient mast cells exhibited increased degranulation and cytokine production after Fc receptor-I cross-linking. In vivo, PIPKI ␣ ϪրϪ mice displayed enhanced passive cutaneous and systemic anaphylaxis. Filamentous actin was diminished in PIPKI ␣ ϪրϪ mast cells, and enhanced degranulation observed in the absence of PIPKI ␣ was also seen in wild-type mast cells treated with latrunculin, a pharmacological inhibitor of actin polymerization. Moreover, the association of Fc RI with lipid rafts and Fc RI-mediated activation of signaling proteins was augmented in PIPKI ␣ ϪրϪ mast cells. Thus, PIPKI ␣ is a negative regulator of Fc RI-mediated cellular responses and anaphylaxis, which functions by controlling the actin cytoskeleton and dynamics of Fc RI signaling. Our results indicate that the different PIPKI isoforms might be functionally specialized.
P110 , a Novel Phosphoinositide 3-KINASE in Leukocytes
Proceedings of the National Academy of Sciences, 1997
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been implicated in signal transduction through tyrosine kinase-and heterotrimeric G-proteinlinked receptors. We report herein the cloning and characterization of p110␦, a novel class I PI3K. Like p110␣ and p110, other class I PI3Ks, p110␦ displays a broad phosphoinositide lipid substrate specificity and interacts with SH2͞SH3 domaincontaining p85 adaptor proteins and with GTP-bound Ras. In contrast to the widely distributed p110␣ and , p110␦ is exclusively found in leukocytes. In these cells, p110␣ and ␦ both associate with the p85␣ and  adaptor subunits and are similarly recruited to activated signaling complexes after treatment with the cytokines interleukin 3 and 4 and stem cell factor. Thus, these class I PI3Ks appear not to be distinguishable at the level of p85 adaptor selection or recruitment to activated receptor complexes. However, distinct biochemical and structural features of p110␦ suggest divergent functional͞regulatory capacities for this PI3K. Unlike p110␣, p110␦ does not phosphorylate p85 but instead harbors an intrinsic autophosphorylation capacity. In addition, the p110␦ catalytic domain contains unique potential proteinprotein interaction modules such as a Pro-rich region and a basic-region leucine-zipper (bZIP)-like domain. Possible selective functions of p110␦ in white blood cells are discussed.