Novel Mechanisms In Dendritic Cells That Promote Th2 and Th17 But Not Th1 Responses In The Lung

摘要: Dendritic cells (DCs) are integral to differentiation of T helper into Th1, Th2 and Th17 subsets. We have dissected two novel pathways in DCs that specifically regulate CD4 cell responses. The first is the role c-Kit-Phosphatidyl inositol 3 kinase (PI3 kinase)-interleukin-6 (IL-6) axis second vascular endothelial growth factor (VEGF). IL-6 plays a central regulating immune responses by limiting Th1 response promoting investigate promote production show allergen house dust mite or mucosal adjuvant cholera toxin but not Th1-inducing adjuvant, CpG oligodeoxynucleotide (ODN) surface expression c-kit its ligand, stem (SCF), DCs. This dual upregulation SCF results sustained PI3-kinase signaling secretion. Intranasal administration antigen mutant mice neutralization blunted promoted lung-draining lymph nodes. lacking functional elicit diminished allergic airway inflammation when adoptively transferred mice. Expression Notch Jagged-2, which has been associated with differentiation, was reduced from generated expressing catalytically inactive form p110ƒO (p110D910A) subunit secrete lower levels upon stimulation CT. These collectively highlight importance c-kit-PI3-kinase-IL-6 responses.We also investigated mechanisms underlying VEGF, recently shown be Th2-skewing cytokine asthma. found CT-stimulated high VEGF while LPS induces minimal production. Activation iNOS, NF-ƒUB PI3 enhanced whereas IL-12, Th1-skewing cytokine, inhibited mechanism highlights critical previously unknown for DC-derived VEGF. Taken together, these findings broaden our understanding diverse enable polarization offer targets therapeutic interventions.