Allergen Challenge Induces Ifng Dependent GTPases in the Lungs as Part of a Th1 Transcriptome Response in a Murine Model of Allergic Asthma 英文参考文献.docVIP

AllergenChallengeInducesIfngDependentGTPasesin theLungsasPartofaTh1TranscriptomeResponseina MurineModelofAllergicAsthma NileshDharajiya1,SwapnilVaidya1,MalaSinha2,BruceLuxon2,IstvanBoldogh3,SanjivSur1* 1DepartmentofInternalMedicine,UniversityofTexasMedicalBranch,Galveston,Texas,UnitedStatesofAmerica,2DepartmentofBiochemistryandMolecularBiology, University of Texas Medical Branch, Galveston, Texas, United States of America, 3Department of Microbiology, University of Texas Medical Branch, Galveston, Texas, UnitedStatesofAmerica Abstract According to the current paradigm, allergic airway inflammation is mediated by Th2 cytokines and pro-inflammatory chemokines. Since allergic inflammation is self-limited, we hypothesized that allergen challenge simultaneously induces anti-inflammatorygenestocounter-balancetheeffectsofTh2cytokinesandchemokines.Toidentifytheseputativeanti- inflammatory genes, we compared the gene expression profile in the lungs of ragweed-sensitized mice four hours after challenge with either PBS or ragweed extract (RWE) using a micro-array platform. Consistent with our hypothesis, RWE challenge concurrently upregulated Th1-associated early target genes of the Il12/Stat4 pathway, such as p47 and p65 GTPases (Iigp, Tgtp and Gbp1), Socs1, Cxcl9, Cxcl10 and Gadd45g with the Th2 genes Il4, Il5, Ccl2 and Ccl7. These Th1- associatedgenesremainupregulatedlongerthantheTh2genes.AugmentationofthelocalTh1milieubyadministrationof Il12orCpGpriortoRWEchallengefurtherupregulatedtheseTh1genes.AbolitionoftheTh1responsebydisruptingthe Ifng gene increased allergic airway inflammation and abrogated RWE challenge-induced upregulation of GTPases, Cxcl9, Cxcl10andSocs1,butnotGadd45g.OurdatademonstratethatallergenchallengeinducestwosetsofTh1-associatedgenes inthelungs:1)Ifng-dependentgenessuchasp47andp65GTPases,Socs1,Cxcl9andCxcl10and2)Ifng-independentTh1- inducing genes like Gadd45g. We propose that allergen-induced airway inflammation is regulated by simultaneous upregulati