The Th2 Cell Cytokines Il-4 and Il-13 Regulate Found in Inflammatory Zone 1/Resistin-Like Molecule Gene Expression by a Stat6 and Ccaat/Enhancer-Binding Protein-Dependent Mechanism

Stutz, A.M.; Pickart, L.A.; Trifilieff, A.; Baumruker, T.; Prieschl-Strassmayr, E.; Woisetschlager, M.

The Journal of Immunology 170(4): 1789-1796


DOI: 10.4049/jimmunol.170.4.1789
Accession: 068488939

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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.