title: TGF-beta and IL-13 synergistically increase eotaxin-1 production in human airway fibroblasts.
abstract: Chronic diseases may involve an "innate" response followed by an adaptive immune response, of a Th1 or Th2 variety. Little is known regarding the interactions of these responses. We hypothesized that TGF-beta1 (innate response factor associated with wound repair) in combination with IL-13 (Th2 factor) might augment inflammatory processes associated with asthma. Airway fibroblasts were cultured from asthmatic subjects and normal controls. These fibroblasts were exposed to TGF-beta1 and IL-13 alone or in combination, and eotaxin-1 expression and production were evaluated. At 48 h, eotaxin-1 production was markedly increased with the combination of TGF-beta1 and IL-13 (p < 0.0001) compared with either stimulus alone. mRNA increased slightly at 1 h with IL-13 or TGF-beta1 plus IL13, peaked, and became significantly increased over IL-13 alone at 24 h. Protein was measurable from 6 h with IL-13 and TGF-beta1 plus IL-13, but greater levels were measured over time with the combination. Actinomycin ablated the increase in mRNA and protein seen with IL-13 alone and with TGF-beta1 plus IL-13. Cycloheximide blocked the increase in mRNA at 6 h in both conditions, but also blocked the increase at 24 h with TGF-beta1 plus IL-13. STAT-6 was rapidly activated with both IL-13 and the combination, without difference. Finally, eotaxin-1-positive fibroblasts were identified in severe asthma biopsies in greater numbers than in normals. These results support the concept that interactions of innate and adaptive immune systems may be important in promoting the tissue eosinophilia of asthma, particularly in those with more severe disease.
authors.affiliation: National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA. wenzels@njc.org
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.forename: John B
authors.initials: JB
authors.lastname: Trudeau
authors.forename: Steve
authors.initials: S
authors.lastname: Barnes
authors.forename: XiuXia
authors.initials: X
authors.lastname: Zhou
authors.forename: Meghan
authors.initials: M
authors.lastname: Cundall
authors.forename: Jay Y
authors.initials: JY
authors.lastname: Westcott
authors.forename: Kelly
authors.initials: K
authors.lastname: McCord
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D001980:Bronchi / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002631:Chemotactic Factors, Eosinophil / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D018793:Interleukin-13; D016209:Interleukin-8; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003609:Dactinomycin; D003513:Cycloheximide