Effect of IL-6 <i>trans</i>-signaling on the pro-remodeling phenotype of airway smooth muscle

Ammit, Alaina J.; Moir, Lyn M.; Oliver, Brian G.; Hughes, Jeffery P.; Alkhouri, Hatem; Ge, Qi; Burgess, Janette K.; Black, Judith L.; Roth, Michael

doi:10.1152/ajplung.00230.2006

Cited by 56 publications

(39 citation statements)

References 57 publications

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“…However, in our microarray experiments, this pathway is upregulated only at IT. Similar conclusions can be drawn for IL-6 signaling pathway, which has also been reported to be involved in asthma pathology (1). Indeed, in the present study, IL-6, gp130 (IL-6st), and IL-6r were found to be upregulated only in IT conditions.…”

Section: Discussionsupporting

confidence: 91%

New asthma biomarkers: lessons from murine models of acute and chronic asthma

Valentin

Crahay²,

Garbacki

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

106

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Many patients suffering from asthma are not fully controlled by currently available treatments, and some of them display an airway remodeling leading to exaggerated lung function decline. The aim of the present study was to unveil new mediators in asthma to better understand pathophysiology and propose or validate new potential therapeutic targets. A mouse model of asthma mimicking acute or chronic asthma disease was used to select genes undergoing a modulation in both acute and chronic conditions. Mice were exposed to ovalbumin or PBS for 1, 5, and 10 wk [short-, intermediate-, and long-term model (ST, IT, and LT)], and gene expression in the lung was studied using an Affymetrix 430 2.0 genome-wide microarray and further confirmed by RT-PCR and immunohistochemistry for selected targets. We report that 598, 1,406, and 117 genes were upregulated and 490, 153, 321 downregulated at ST, IT, and LT, respectively. Genes related to mucous secretion displayed a progressively amplified expression during the allergen exposure protocol, whereas genes corresponding to growth and differentiation factors, matrix metalloproteinases, and collagens were mainly upregulated at IT. By contrast, genes related to cell division were upregulated at ST and IT and were downregulated at LT. In this study, besides confirming that Arg1, Slc26a4, Ear11, and Mmp12 genes are highly modulated throughout the asthma pathology, we show for the first time that Agr2, Scin, and Cd209e genes are overexpressed throughout the allergen exposure and might therefore be considered as suitable new potential targets for the treatment of asthma.

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Section: Discussionsupporting

confidence: 91%

New asthma biomarkers: lessons from murine models of acute and chronic asthma

Valentin

Crahay²,

Garbacki

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

106

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“…In contrast, HASM cells are also known to produce and release IL-6, a pleiotropic cytokine known to have proinflammatory actions in asthma (47). IL-6 is found in increased amounts in induced sputum of asthmatic patients after mast cell activation (48) and in the sputum, exhaled breath, and plasma of patients with COPD (49).…”

Section: Discussionmentioning

confidence: 99%

Thymic Stromal Lymphopoietin Receptor-Mediated IL-6 and CC/CXC Chemokines Expression in Human Airway Smooth Muscle Cells: Role of MAPKs (ERK1/2, p38, and JNK) and STAT3 Pathways

Shan¹,

Redhu²,

Saleh³

et al. 2010

The Journal of Immunology

112

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Thymic stromal lymphopoietin (TSLP) plays a pivotal role in allergic diseases such as asthma, chronic obstructive pulmonary disease, and atopic dermatitis. Enhanced TSLP expression has been detected in asthmatic airways that correlated with both the expression of Th2-attracting chemokines and with disease severity. Although cumulative evidence suggests that human airway smooth muscle (HASM) cells can initiate or perpetuate the airway inflammation by secreting a variety of inflammatory cell products such as cytokines and chemokines, the role of TSLP in this pathway is not known. In the current study, we sought to investigate whether HASM cells express the TSLP receptor (TSLPR) and whether it is functional. We first demonstrated that primary HASM cells express the transcript and protein of both TSLPR subunits (TSLPR and IL-7Rα). Functionally, TSLPR-mediated HASM activation induced a significant increase in CXC (IL-8/CXCL8), CC (eotaxin-1/CCL11) chemokines, and proinflammatory cytokine IL-6 expression. Furthermore, using biochemical and genetic approaches, we found that TSLP-induced proinflammatory gene expression in HASM involved the transcriptional mechanisms, MAPKs (ERK1/2, p38, and JNK), and STAT3 activation. Finally, TSLPR immunoreactivity in bronchial sections from mild allergic asthmatics suggested the potential in vivo TSLP targeting of HASM. Altogether, our data suggest that the TSLPR-mediated HASM activation induces proinflammatory cytokine and chemokines release that may facilitate inflammatory immune cells recruitment in airways. In addition, it may be inferred that TSLPR is involved in the pathogenesis of allergic asthma through the activation of HASM cells by TSLP.

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“…There has been a disagreement in the literature whether HASM cells express IL-6 receptors and whether HASM cells are responsive to IL-6 alone (1,39). Expression of IL6R was first confirmed in all six cell lines of HASM cells by RNAseq at baseline and 24-h time points (data not shown).…”

Section: Kinetics Of Activation and Functional Effects Of Classical Il-6mentioning

confidence: 99%

“…ASM cells express receptors for a variety of cytokines, namely IL-13, IL-1␤, and TNF-␣ (73), and exposure of ASM cells to inflammatory cytokines results in significant changes in the expression of genes and cell functions (contraction, relaxation, secretion, migration) (9). There are conflicting reports whether ASM cells express the IL-6 receptor (1,39). Furthermore, the effects of classical IL-6 signaling and IL-6 trans-signaling in ASM have not been thoroughly investigated.…”

mentioning

confidence: 99%

IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle

Robinson

Deshpande

Chou

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle

Abstract: Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle.

Cited by 56 publications

References 57 publications

New asthma biomarkers: lessons from murine models of acute and chronic asthma

New asthma biomarkers: lessons from murine models of acute and chronic asthma

Thymic Stromal Lymphopoietin Receptor-Mediated IL-6 and CC/CXC Chemokines Expression in Human Airway Smooth Muscle Cells: Role of MAPKs (ERK1/2, p38, and JNK) and STAT3 Pathways

IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle

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