Granulocyte macrophage colony-stimulating factor-driven respiratory mucosal sensitization induces Th2 differentiation and function independently of interleukin-4.
The development of T helper (Th)2 responses is a key step in the pathogenesis of asthma. Interleukin (IL)-4 is thought to be important, although not strictly necessary, for Th2 differentiation, although triggers of IL-4-independent Th2 polarization have not been identified. We examined whether IL-4 is necessary for Th2-polarized responses during granulocyte macrophage colony-stimulating factor (GM-CSF)-driven respiratory mucosal sensitization. Balb/c wild type (WT) or IL-4 knockout (4KO) mice were exposed to aerosolized ovalbumin (OVA) in the context of airway GM-CSF expression. We examined the extent of Th2 polarization using real-time quantitative polymerase chain reaction on lymph node mRNA, flow cytometric analysis of lung Th cells, and measurement of cells, cytokines, and immunoglobulins in bronchoalveolar lavage (BAL) and serum. GATA-3 and CCR3, -4, and -8 were expressed in the lymph nodes of WT and 4KO mice at similar levels, as were IL-5 and IL-13 levels in the BAL, T1/ST2 on lung Th cells, and BAL eosinophils after recall challenge. With the exception of immunoglobulin production, expression of GATA-3, CCR-3, -4, -8, IL-5, and T1/ST2, and the generation of blood eosinophilia, were intact in mice doubly deficient in both IL-4 and IL-13. We conclude that IL-4 is not required for the generation of Th2-polarized responses in the presence of GM-CSF.
D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D007136:Immunoglobulins / Q000096:biosynthesis; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000473:pathology*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000378:metabolism; D020545:Respiratory Mucosa / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
C515350:CCR3 protein, human; C515354:CCR4 protein, human; C103330:CCR8 protein, human; C515351:Ccr3 protein, mouse; C515355:Ccr4 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007136:Immunoglobulins; D018793:Interleukin-13; D015848:Interleukin-5; D012333:RNA, Messenger; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D015534:Trans-Activators; D015847:Interleukin-4; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor