Induction of Uteroglobin-Related Protein 2 (<i>Ugrp2</i>) Gene Expression by the Th2 Cytokines IL-4 and IL-13

Yamada, Atsushi; Sheikh, Faruk; Niimi, Tomoaki; DeMayo, Francesco J.; Keegan, Achsah; Donnelly, Raymond P.; Kimura, Shioko

doi:10.4049/jimmunol.175.9.5708

Cited by 18 publications

(37 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, several reports have described the modulation of gene expression in Clara cells by the Th2 cytokines IL-4 and IL-13 [33,34]. Ablation of nuclear factor-kB signalling in Clara cells reduces peribronchial fibrosis, CD4+ cell infiltration, airway mucus, CCL17 and eotaxin release and eosinophils in allergen-challenged mice [34,35]. Together, these and other studies demonstrate that epithelial cells have the ability to respond and orchestrate lung immune responses.…”

Section: Discussionmentioning

confidence: 70%

“…Additionally, the expression of pattern recognition receptors, such as Toll-like receptor 4, on the lung epithelium has a critical role for the activation of dendritic cells (DC) in allergic lung inflammation, stressing the importance of the lung tissue microenvironment for efficient Tcell activation [32]. Moreover, several reports have described the modulation of gene expression in Clara cells by the Th2 cytokines IL-4 and IL-13 [33,34]. Ablation of nuclear factor-kB signalling in Clara cells reduces peribronchial fibrosis, CD4+ cell infiltration, airway mucus, CCL17 and eotaxin release and eosinophils in allergen-challenged mice [34,35].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clara cells drive eosinophil accumulation in allergic asthma

Sonar

Ehmke²,

Marsh³

et al. 2011

Eur Respir J

View full text Add to dashboard Cite

Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the ''immunomodulatory barrier'' of the airway epithelium.To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model. Mice were sensitised with subcutaneous injections of 10 mg endotoxin-free ovalbumin in conjunction with naphthaleneinduced Clara cell depletion.Clara epithelial cell depletion in the lung strongly reduced eosinophil influx, which correlated with decreased eotaxin levels and, moreover, diminished the T-helper cell type 2 inflammatory response, including interleukin (IL)-4, IL-5 and IL-13. In contrast, airway hyperresponsiveness was increased. Further investigation revealed Clara cells as the principal source of eotaxin in the lung.These findings are the first to show that Clara airway epithelial cells substantially contribute to the infiltration of eotaxin-responsive CCR3+ immune cells and augment the allergic immune response in the lung. The present study identifies Clara cells as a potential therapeutic target in inflammatory lung diseases such as allergic asthma.

show abstract

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Clara cells drive eosinophil accumulation in allergic asthma

Sonar

Ehmke²,

Marsh³

et al. 2011

Eur Respir J

View full text Add to dashboard Cite

show abstract

“…This core palindromic sequence matches the consensus sequence for DNA binding used by all of the Stat transcription factors, including Stat6 and Stat1. Recently, Yamada et al (30) found that both Stat1 and Stat6 bind to the same Stat factor binding element in the promoter of the IL-4-and IL-13-responsive Ugrp2 gene and that activation of Stat1 decreased the binding of Stat6 to the site. One mechanism to explain our findings of the opposing effects of Stat1 and Stat6 on IL-13-induced PDGF-A and PDGF-C is that there exists a competition between Stat1 and Stat6 for binding to the Stat factorbinding element in the Egr-1 promoter.…”

Section: Discussionmentioning

confidence: 99%

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

Ingram

Antao-Menezes

Mangum

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

IL-13 is a key cytokine involved in airway remodeling in asthma. We previously reported that IL-13 stimulated the mitogenesis of lung fibroblasts via platelet-derived growth factor (PDGF)-AA. In this report, we show that IL-13 increases PDGF-A and PDGF-C mRNA levels through a dual intracellular cascade that requires coactivation of Stat6 and Stat1 to impact transcriptional regulation of the early growth response (Egr)-1 gene, which then drives PDGF expression. Increased levels of PDGF-AA and PDGF-CC protein were observed in vivo in the airways of IL-13 transgenic mice. IL-13 up-regulated PDGF-A and PDGF-C mRNA levels in lung fibroblasts isolated from three different background strains of mice. However, IL-13-induced PDGF-A and PDGF-C mRNA levels were significantly reduced in Stat6-deficient (Stat6−/−) fibroblasts as compared with wild-type Stat6+/+ fibroblasts. In contrast, IL-13-induced PDGF-A and PDGF-C mRNAs were enhanced in Stat1−/− fibroblasts as compared with Stat1+/+ fibroblasts. IL-13 did not up-regulate PDGF-A or PDGF-C mRNA levels in Egr-1−/− fibroblasts. Moreover, IL-13 did not increase Egr-1 mRNA and protein levels in Stat6−/− fibroblasts and yet enhanced Egr-1 mRNA and protein levels in Stat1−/− fibroblasts. Our findings support the hypothesis that Stat6 and Stat1 exert stimulatory and inhibitory effects on Egr-1 and PDGF ligand mRNA transcription, respectively. This novel mechanism could aid in identifying molecular targets for the treatment of chronic airway remodeling and fibrosis in asthma.

show abstract

“…A double-stranded oligonucleotide (21 nt) probe was prepared based on the STAT-binding DNA sequence present in the mouse Ugrp2 gene promoter (12), and used as a probe in the gel-shift assays. Binding reactions were performed at room temperature for 30 minutes by incubating radiolabeled probe DNA (.…”

Section: Electrophoretic Mobility Shift Analysismentioning

confidence: 99%

“…Involvement of the AKT pathway is also implicated in epidermal growth factor (EGF) and transforming growth factor (TGF)-a-induced SCGB3A1 expression (11). Further, the Th2 cytokines IL-4 and IL-13 induce SCGB3A1 expression, suggesting that this gene may potentially play a role in the pathogenesis of inflammatory lung diseases (12). In this respect, the involvement of SCGB3A2, a homologous gene to SCGB3A1, in lung inflammation has been described; proinflammatory cytokines IL-5 and IL-9 reduce SCGB3A2 expression (13,14), whereas anti-inflammatory cytokine IL-10 enhances expression (15).…”

mentioning

confidence: 99%

Oncostatin M Regulates Secretoglobin 3A1 and 3A2 Expression in a Bidirectional Manner

Tomita

Yamada²,

Miyakoshi³

et al. 2009

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Secretoglobin (SCGB) 3A1 and 3A2 are members of the small molecular weight secretoglobin gene superfamily. SCGB3A1 is a tumor suppressor gene, whereas SCGB3A2 has anti-inflammatory properties. Both genes are mainly expressed in the lung and trachea in mice. Whether the expression and/or function of these two genes are related is not known. Here we show that the expression of SCGB3A1 and SCGB3A2 are bidirectionally regulated by oncostatin M (OSM) when examined in a mouse transformed Clara cell line (mtCC); SCGB3A1 is up-regulated by OSM, while SCGB3A2 is downregulated in a time-and dose-dependent manner. OSM-activated STAT3/5, through binding to the STAT-binding element located at 2201 to 2209 bp in the mouse Scgb3a1 gene promoter, and the extracellular signal-regulated kinase (ERK)-and p38-mitogenactivated protein kinase (MAPK) pathways are responsible for the OSM-induced up-regulation of SCGB3A1 expression. On the other hand, the 2113 to 2273 bp region in the Scgb3a2 promoter appears to be responsible for the OSM induced down-regulation of the gene. No significant differences in the levels or patterns of specific DNAbinding proteins were found in the 2113 to 2273 bp region as determined by electrophoretic mobility shift assays. Neither the ERK-nor p38-MAPK pathways were involved in the OSM-induced reduction of Scgb3a2 promoter activity. These results suggest that OSM-induced suppression of SCGB3A2 expression is an indirect effect of OSM. Expression of the Clara cell marker, CYP2F2, was markedly decreased upon OSM treatment in parallel with the decrease of SCGB3A2 expression in mtCC cells. The differential regulation of Scgb3a1 and Scgb3a2 gene expression by OSM may explain the unique functions of these genes in the lung.

show abstract

Induction of Uteroglobin-Related Protein 2 (Ugrp2) Gene Expression by the Th2 Cytokines IL-4 and IL-13

Cited by 18 publications

References 60 publications

Clara cells drive eosinophil accumulation in allergic asthma

Clara cells drive eosinophil accumulation in allergic asthma

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

Oncostatin M Regulates Secretoglobin 3A1 and 3A2 Expression in a Bidirectional Manner

Contact Info

Product

Resources

About