Role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation.
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 p110delta 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 p110delta mutants, whereas type 1 cytokine responses (IFN-gamma and CXCL10) were robust. Elevated IFN-gamma production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-gamma 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 p110delta-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110delta-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110delta signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease.
Nashed
Baher F
BF
CIHR National Training Program in Allergy and Asthma Research and Department of Immunology, University of Manitoba, Winnipeg, Canada.
Zhang
Tingting
T
Al-Alwan
Monther
M
Srinivasan
Ganesh
G
Halayko
Andrew J
AJ
Okkenhaug
Klaus
K
Vanhaesebroeck
Bart
B
Hayglass
Kent T
KT
Marshall
Aaron J
AJ
D019870:1-Phosphatidylinositol 4-Kinase / Q000276:immunology* / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology; D007527:Isoenzymes / Q000172:deficiency / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D011657:Pulmonary Eosinophilia / Q000201:enzymology / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000201:enzymology* / Q000276:immunology
D016207:Cytokines; D007527:Isoenzymes; D019870:1-Phosphatidylinositol 4-Kinase