The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone 1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism.
The onset of allergic inflammation in the lung is driven by a complex genetic program. This study shows that found in inflammatory zone (FIZZ)1 and FIZZ2, but not FIZZ3, gene expression was up-regulated 6 h after Ag challenge in a mouse model of acute pulmonary inflammation. Induction of both genes was abolished in allergen-challenged STAT6-deficient mice. FIZZ1, but not FIZZ2, mRNA was up-regulated upon incubation of the myeloid cell line BMnot with IL-4. The promoter region of FIZZ1 contains functional binding sites for STAT6 and C/EBP. FIZZ1 promoter reporter gene constructs responded to IL-4 and IL-13 stimulation in transiently transfected cells. Point mutations in the STAT6 or the C/EBP site led to loss of cytokine responsiveness indicating that IL-4-mediated induction of murine FIZZ1 is orchestrated by the coordinate action of STAT6 and C/EBP. It is concluded that the expression of the genes encoding FIZZ1 and FIZZ2, but not FIZZ3, is induced in allergen-challenged lungs in a STAT6-dependent fashion. STAT6 directly regulates IL-4- and IL-13-triggered induction of FIZZ1 expression at the transcriptional level by cooperation with C/EBP. Induction of FIZZ2 gene expression most likely occurs independent of a direct effect by these cytokines and may be due to indirect STAT6-driven mechanisms.
Stütz
Adrian M
AM
Department of Allergic Diseases, Novartis Research Institute, Brunnerstrasse 59, A-1630 Vienna, Austria.
Pickart
Louise A
LA
Trifilieff
Alexandre
A
Baumruker
Thomas
T
Prieschl-Strassmayr
Eva
E
Woisetschläger
Maximilian
M
D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006729:Hormones, Ectopic / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020932:Nerve Growth Factor; D011401:Promoter Regions, Genetic / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D051381:Rats; D052243:Resistin; D050800:STAT6 Transcription Factor; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000941:Antigens; D022762:CCAAT-Enhancer-Binding Proteins; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D011506:Proteins; D052243:Resistin; C499623:Retn protein, mouse; C499622:Retn protein, rat; C413576:Retnla protein, mouse; C486575:Retnla protein, rat; C486522:Retnlb protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D020932:Nerve Growth Factor