TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism.
The diverse functions of macrophages as participants in innate and acquired immune responses are regulated by the specific milieu of environmental factors, cytokines, and other signaling molecules that are encountered at sites of inflammation. Microarray analysis of the transcriptional response of mouse peritoneal macrophages to the T(H)2 cytokine interleukin-4 (IL-4) identified Ym1 and arginase as the most highly up-regulated genes, exhibiting more than 68- and 88-fold induction, respectively. Molecular characterization of the Ym1 promoter in transfected epithelial and macrophage cell lines revealed the presence of multiple signal transducers and activators of transcription 6 (STAT6) response elements that function in a combinatorial manner to mediate transcriptional responses to IL-4. The participation of STAT6 as an obligate component of protein complexes binding to these sites was established by analysis of nuclear extracts derived from STAT6-deficient macrophages. Macrophage expression of Ym1 was highly induced in vivo by an IL-4- and STAT6-dependent mechanism during the evolution of allergic peritonitis, supporting the biological relevance of the IL-4-dependent pathway characterized ex vivo in peritoneal macrophages. These studies establish Ym1 as a highly inducible STAT6-dependent transcript in T(H)2-biased inflammation and define Cis-active elements in the Ym1 promoter that are required for this transcriptional response.
Welch
John S
JS
Department of Cellular and Molecular Medicine, La Jolla, California 92093-0651, USA.
Escoubet-Lozach
Laure
L
Sykes
David B
DB
Liddiard
Kate
K
Greaves
David R
DR
Glass
Christopher K
CK
D000818:Animals; D001119:Arginase / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology*; D018793:Interleukin-13 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics*; D037102:Lectins / Q000235:genetics*; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010538:Peritonitis / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism*; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics*
D017931:DNA Primers; D018793:Interleukin-13; D015850:Interleukin-6; D037102:Lectins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases; D001119:Arginase