Suppressive Effect of IL-4 on IL-13-Induced Genes in Mouse Lung

Finkelman, Fred D.; Yang, Mingyan; Perkins, Charles; Schleifer, Kathleen W.; Sproles, Alyssa; Santeliz, Jo Anna; Bernstein, Jonathan A.; Rothenberg, Marc E.; Morris, Suzanne C.; Wills‐Karp, Marsha

doi:10.4049/jimmunol.174.8.4630

Cited by 44 publications

(39 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In an experimental model using intratracheal delivery of cytokines, IL-4, but not IL-13, induced IFN-␥ expression (26). Consistent with this, IFN-␥ levels remain relatively unchanged throughout our resolution model (data not shown), suggesting an alternative mechanism induced by chronic IL-13 expression for induction or accumulation of CXCL9 and CXCL10 mRNA.…”

Section: Discussionsupporting

confidence: 70%

Persistent Effects Induced by IL-13 in the Lung

Fulkerson

Fischetti

Hassman

et al. 2006

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

IL-13 overexpression in the lung induces inflammatory and remodeling responses that are prominent features of asthma. Whereas most studies have concentrated on the development of IL-13-induced disease, far fewer studies have focused on the reversibility of IL-13-induced pathologies. This is particularly important because current asthma therapy appears to be poor at reversing lung remodeling. In this manuscript, we used an externally regulatable transgenic system that targets expression of IL-13 to the lung with the aim of characterizing the reversibility process. After 4 wk of doxycycline (dox) exposure, IL-13 expression resulted in mixed inflammatory cell infiltration, mucus cell metaplasia, lung fibrosis, and airspace enlargement (emphysema). After withdrawal of dox, IL-13 protein levels were profoundly reduced by 7 d and below baseline by 14 d. During this time frame, the level of lung eosinophils returned to near normal, whereas macrophages, lymphocytes, and neutrophils remained markedly elevated. IL-13-induced mucus cell metaplasia significantly decreased (91%) 3 wk after withdrawal of dox, showing strong correlation with reduced eosinophil levels. In contrast, IL-13-induced lung fibrosis did not significantly decline 4 wk after dox withdrawal. Importantly, IL-13-induced emphysema persisted, but modestly declined 4 wk after dox. Examination of transcript expression profiles identified a subset of genes that remained increased weeks after transgene expression was no longer detected. Notably, numerous IL-13-induced cytokines and enzymes were reversible (IL-6 and cathepsins), whereas others were sustained (CCL6 and chitinases) after IL-13 withdrawal, respectively. Thus, several hallmark features of IL-13-induced lung pathology persist and are dissociated from eosinophilia after IL-13 overexpression ceases.Keywords: asthma; cytokines; eosinophils; inflammation; lung Allergic asthma is characterized by chronic inflammation of the airways, airway wall remodeling, and a decline in respiratory function. In asthma, structural changes in the airway include mucus cell metaplasia, increased deposition of extracellular matrix proteins (e.g., collagen and proteoglycans), and hyperplasia of myofibroblasts and smooth muscle cells (1, 2). Airway remodeling and persistent inflammation contribute to disease pathogenesis of asthma. Animal studies have defined a critical effector role for IL-13 in many pathologic features of experimental asthma, including airway inflammation, tissue fibrosis, and mucus hypersecretion by goblet cells (3-5).The effector functions mediated by IL-13 include a diverse array of biological activities (6). IL-13-deficient animals, novel IL-13 antagonists, and transgenic overexpression modeling sys- tems have successfully defined a central role for IL-13 in some inflammatory diseases of the lung (6). In animal models, pulmonary overexpression of IL-13 results in inflammation, airway fibrosis, mucus metaplasia, airway hyperresponsiveness, and enhanced lung volumes and compliance (5, 7). The inflammatory ...

show abstract

Section: Discussionsupporting

confidence: 70%

Persistent Effects Induced by IL-13 in the Lung

Fulkerson

Fischetti

Hassman

et al. 2006

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…The SPRR2A protein was also reported to be highly induced in gastric mucosa upon Helicobacter pylori infection in the human stomach [31]. And SPRR genes are activated during IL-13 mediated immune response in the lung [32]. The female mouse accepts copulation only at the estrous stage, which will introduce pathogens to the vagina and uterus; meanwhile, the sperms may cause the changes of the physiological environment in the uterus.…”

Section: Discussionmentioning

confidence: 99%

“…Wet membranes were crosslinked by an ultraviolet crosslinker for 8 s. The pGEM-T easy vectors containing the cDNA fragments of sprr2a, 2f or gapdh genes were used to generate [α− 32 …”

Section: Northern Blot Analysismentioning

confidence: 99%

Gene expression pattern and hormonal regulation of Small Proline-Rich Protein 2 family members in the female mouse reproductive system during the estrous cycle and pregnancy

Tan

Sun

et al. 2006

Reprod. Nutr. Dev.

View full text Add to dashboard Cite

-Small proline-rich proteins (SPRR) are known to construct the cornified cell envelope (CE) in the stratified squamous epithelial cell. Their functions in the simple epithelium such as the uterine epithelium are not clear hitherto. In the present study, the mRNA expression patterns of sprr2 family members in the mouse uterus and vagina during the estrous cycle and pregnancy as well as their regulation by steroids were investigated. Using semi-quantitative RT-PCR, it was revealed that the transcripts of sprr2b, 2e and 2g genes were up-regulated in the proestrous and estrous uteri, and sprr2d was up-regulated only in the estrous uterus. In the vagina, transcription of sprr2a, 2b, 2d, 2e and 2k genes were up-regulated at the metestrous stage. Northern blot analysis demonstrated that the overall expression of sprr2 was highly up-regulated in the estrous uterus and the metestrous vagina. During pregnancy, the sprr2 mRNA in the uterus was sharply repressed from day 3 postcoitus on, and began to be induced around labor time. In situ hybridization showed that the sprr2 transcripts were localized in uterine luminal and glandular epithelial cells as well as vaginal stratified epithelial cells. In ovariectomized mice, the expression of sprr2a, 2d, 2e and 2f genes in the uterus were induced by estrogen, and the effect of estrogen on sprr2d and 2e expression could be partly abolished by progesterone. The data indicate that the sprr2 genes have unique regulation patterns in different reproductive tissues under different physiological conditions, and the encoded proteins might play diverse functions in the female reproductive system. small proline-rich protein / uterus / estrous cycle / pregnancy / stress

show abstract

“…with this treated serum or, as a control, with serum from N. brasiliensis-infected IL-13/sIL-13R␣2-double deficient mice. Extracts from the lungs of both sets of mice were first tested for RNA specific for the Sprr1, Sprr2a, and Sprr2b genes, which are potently induced by IL-13 to a considerably greater extent than they are induced by IL-4 (38). No increase in the expression of these genes was observed in two experiments (data not shown), suggesting that IL-13/sIL-13R␣2 complexes lack IL-13 activity.…”

Section: Il-13/sil-13r␣2 Complexes Are Acid Stable and May Suppress Imentioning

confidence: 99%

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

Khodoun

Lewis²,

Yang

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4Rα and sIL-13Rα2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4Rα complexes rapidly dissociate, releasing active IL-4, whereas sIL-13Rα2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13Rα2, IL-4, or sIL-4Rα. Approximately 25% of sIL-13Rα2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13Rα2 in serum increase considerably during a Th2 response. sIL-13Rα2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4Rα-dependent while the effect of IL-13 is partially IL-4Rα-independent. Inhalation of an IL-13/sIL-13Rα2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4Rα predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13Rα2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.

show abstract

Suppressive Effect of IL-4 on IL-13-Induced Genes in Mouse Lung

Cited by 44 publications

References 67 publications

Persistent Effects Induced by IL-13 in the Lung

Persistent Effects Induced by IL-13 in the Lung

Gene expression pattern and hormonal regulation of Small Proline-Rich Protein 2 family members in the female mouse reproductive system during the estrous cycle and pregnancy

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

Contact Info

Product

Resources

About