A stage-specific functional role of the leucine zipper transcription factor c-Maf in lung Th2 cell differentiation.
The transcription factor c-Maf controls IL-4 gene expression in CD4(+) T cells, and its expression is up-regulated in human asthmatic airways after allergen challenge. In the present study, we addressed the role of c-Maf in asthma by studying transgenic (Tg) mice overexpressing c-Maf in CD4(+) T cells under the control of the CD2 promoter. As shown, lung CD4(+) T cells of c-maf-Tg mice produced more IL-5 at the early stage (day 2) of culture in the presence of IL-4 than wild-type control cells. Consistently, c-maf-Tg mice spontaneously showed increased IL-5 expression and eosinophils in the bronchial alveolar lavage fluid (BALF) and activated IL-5 signal transduction via Raf-1 and Ras in lung eosinophils. Finally, IL-13 was suppressed in the BALF of c-maf-Tg mice and in supernatants of Tg lung CD4(+) T cells cultured in the presence of IL-2. Consistently, retroviral overexpression of c-Maf suppressed IL-13 production in developing lung Th2 cells. In summary, c-Maf induces IL-5 production in lung CD4(+) T cells at an early stage, but along with IL-2 suppresses IL-13 production in differentiating lung Th2 cells, thereby explaining the finding that overexpression of c-Maf does not cause airway hyperresponsiveness, a hallmark feature of asthma.
Hausding
Michael
M
Laboratory of Cellular and Molecular Lung Immunology, I Medical Clinic, Mainz, Germany.
Ho
I-Cheng
IC
Lehr
Hans A
HA
Weigmann
B
B
Lux
Christine
C
Schipp
Mechtild
M
Galle
Peter R
PR
Finotto
Susetta
S
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004804:Eosinophils / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D016350:Leucine Zippers / Q000502:physiology*; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D015848:Interleukin-5; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D014157:Transcription Factors; D015847:Interleukin-4