title: Suppressive effect of IL-4 on IL-13-induced genes in mouse lung.
abstract: Although IL-4 signals through two receptors, IL-4R alpha/common gamma-chain (gamma(c)) and IL-4R alpha/IL-13R alpha1, and only the latter is also activated by IL-13, IL-13 contributes more than IL-4 to goblet cell hyperplasia and airway hyperresponsiveness in murine asthma. To determine whether unique gene induction by IL-13 might contribute to its greater proasthmatic effects, mice were inoculated intratracheally with IL-4 or IL-13, and pulmonary gene induction was compared by gene microarray and real-time PCR. Only the collagen alpha2 type VI (Ca2T6) gene and three small proline-rich protein (SPRR) genes were reproducibly induced > 4-fold more by IL-13 than by IL-4. Preferential IL-13 gene induction was not attributable to B cells, T cells, or differences in cytokine potency. IL-4 signaling through IL-4R alpha/gamma(c) suppresses Ca2T6 and SPRR gene expression in normal mice and induces these genes in RAG2/gamma(c)-deficient mice. Although IL-4, but not IL-13, induces IL-12 and IFN-gamma, which suppress many effects of IL-4, IL-12 suppresses only the Ca2T6 gene, and IL-4-induced IFN-gamma production does not suppress the Ca2T6 or SPRR genes. Thus, IL-4 induces genes in addition to IL-12 that suppress STAT6-mediated SPRR gene induction. These results provide a potential explanation for the dominant role of IL-13 in induction of goblet cell hyperplasia and airway hyperresponsiveness in asthma.
authors.affiliation: Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. ffinkelman@pol.net
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: Mingyan
authors.initials: M
authors.lastname: Yang
authors.forename: Charles
authors.initials: C
authors.lastname: Perkins
authors.forename: Kathleen
authors.initials: K
authors.lastname: Schleifer
authors.forename: Alyssa
authors.initials: A
authors.lastname: Sproles
authors.forename: Joanna
authors.initials: J
authors.lastname: Santeliz
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Morris
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
mesh_terms: D000818:Animals; D001483:Base Sequence; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000235:genetics / Q000276:immunology; D024142:Collagen Type VI / Q000235:genetics; D055233:Cornified Envelope Proline-Rich Proteins; D016207:Cytokines / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D018793:Interleukin-13 / Q000235:genetics / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics / Q000494:pharmacology*; D053662:Interleukin-4 Receptor alpha Subunit; D008168:Lung / Q000187:drug effects* / Q000276:immunology* / Q000503:physiopathology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D024142:Collagen Type VI; D055233:Cornified Envelope Proline-Rich Proteins; D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C504000:IL4R protein, human; C504002:Il4ra protein, mouse; D018793:Interleukin-13; D053662:Interleukin-4 Receptor alpha Subunit; D008565:Membrane Proteins; D011506:Proteins; C499308:Rag2 protein, mouse; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; C064655:V(D)J recombination activating protein 2; D015847:Interleukin-4