IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis

Huang, Min; Sharma, Sherven; Zhu, Li; Keane, Michael P.; Luo, Jie; Zhang, Ling; Burdick, Marie D.; Lin, Ying Q.; Dohadwala, Mariam; Gardner, Brian; Batra, Raj K.; Strieter, Robert M.; Dubinett, Steven M.

doi:10.1172/jci14685

Cited by 64 publications

(32 citation statements)

References 43 publications

(58 reference statements)

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“…Another potential cellular target is macrophages. The critical profibrotic mediator TGF-β can derive from a variety of cell types, including fibroblasts themselves (63)(64)(65)(66). Our data with fibroblast-specific FOXM1-knockout mice implicate a role for the fibroblast in the generation of this mediator, along with the TGF-β target gene product CTGF.…”

Section: Discussionmentioning

confidence: 59%

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

Penke

Speth

Dommeti

et al. 2018

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 59%

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

Penke

Speth

Dommeti

et al. 2018

Journal of Clinical Investigation

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“…In chronic inflammatory conditions, resident fibroblasts and macrophages, and infiltrating Treg cells locally produce TGF-β [35]. Acidic conditions in inflamed sites and the presence of reactive oxygen species may be involved in the activation of TGF-β [36].…”

Section: Discussionmentioning

confidence: 99%

TGF‐β induces the differentiation of human CXCL13‐producing CD4⁺ T cells

et al. 2015

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In the ectopic lymphoid‐like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4+ T cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF‐β induces the differentiation of human CXCL13‐producing CD4+ T cells from naïve CD4+ T cells. The TGF‐β‐induced CXCL13‐producing CD4+ T cells do not express CXCR5, B‐cell lymphoma 6 (BCL6), and other Tfh‐cell markers. Furthermore, expression levels of CD25 (IL‐2Rα) in CXCL13‐producing CD4+ T cells are significantly lower than those in FoxP3+ in vitro induced Treg cells. Consistent with this, neutralization of IL‐2 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4+ T cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in naïve CD4+ T cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13‐producing CD4+ T cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13‐producing CD4+ T cells. Our findings demonstrate that CXCL13‐producing CD4+ T cells lacking Tfh‐cell features differentiate via TGF‐β signaling but not via FoxP3, and exert their function in IL‐2‐limited but TGF‐β‐rich and proinflammatory cytokine‐rich inflammatory conditions.

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“…Since Smad7 suppresses TGF-β signaling through preventing phosphorylation of smad2/3 and mediating degradation of TGF-β receptor [9,10], the observation places Smad7 in a remarkable position of AD. The expression of Smad7 is upregulated by stimulation of multiple signals, such as activation of STAT1 pathway by IFN-γ or IL-7 and activation of NF-κB pathway by TNF-α [41][42][43]. Furthermore, overexpression of Smad7 has been reported in several inflammatory diseases, such as inflammatory bowel disease [44], multiple sclerosis [45] and Helicobacter pyloriassociated gastritis [46].…”

Section: Discussionmentioning

confidence: 99%

Attenuated TGF‐β1 responsiveness of dendritic cells and their precursors in atopic dermatitis

et al. 2013

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The responsiveness of DCs and their precursors to transforming growth factor beta1 (TGF-β1) affects the nature of differentiating DC subsets, which are essential for the severity of atopic dermatitis (AD). To evaluate TGF-β signaling in monocytes and monocytederived DCs of AD patients compared with that of controls, in vitro generated Langerhans cell (LC) like DCs, expression of TGF-β receptors, phospho-Smad2/3 and Smad7 were evaluated. Furthermore, TNF-α expression and synergistic effects of TNF-α upon TGF-β signaling and DC generation were evaluated. We found LC-like DC differentiation of monocytes from AD patients in response to TGF-β1 was remarkably reduced and TGF-β1 receptor expression was significantly lower compared with that of healthy controls. Attenuated TGF-β1 responsiveness mirrored by lower phospho-Smad2/3 expression after TGF-β1 stimulation and higher expression of inhibitory Smad7 was observed in monocytes from AD patients. During DC generation, mRNA expression of Smad7 was relatively higher in LC-like DCs of AD patients. Lower TNF-α expression of monocytes from AD patients might further contribute to attenuated TGF-β signaling in the disease since TNF-α had synergistic effects on TGF-β1 signaling and LC generation through mediating the degradation of Smad7. Our results demonstrate alleviated TGF-β1 signaling together with the amount of soluble co-factors might direct the nature of differentiating DCs.Keywords: Atopic dermatitis r Dendritic cells r Monocytes r TNF-α r TGF-β IntroductionAtopic dermatitis (AD) is one of the most common allergic inflammatory skin diseases affecting up to 20% of children and up to 3% of adults in the western society [1]. It has been shown that the interaction of inherited as well as environmental factors plays an important role in the pathogenesis of AD [1,2].Transforming growth factor beta1 (TGF-β1) is a multifunctional cytokine and TGF-β1 signaling is essential for the maintenance of immune tolerance [3]. Briefly, TGF-β1 signaling is initiated by binding of TGF-β1 to its heterodimeric transmembrane receptor complex, which is composed of type I (TGFβRI) and Correspondence: Prof. Natalija Novak e-mail: Natalija.Novak@ukb.uni-bonn.de type II (TGFβRII) receptors [4]. Binding of TGF-β1 results in the phosphorylation and activation of TGFβRI, which then activates TGFβRII [4]. The activated TGF-β receptors induce phosphorylation of Smad2 and Smad3 [5,6], which form a complex together with Smad4. The complex translocates into the nucleus and starts gene transcription and regulation [5][6][7][8]. The type III (TGFβRIII) receptor does not have signaling function but helps TGF-β to bind its receptors. Importantly, TGF-β1 signaling is suppressed by the expression of inhibitory Smad molecules, namely Smad7, which mediates degradation of TGFβRI and suppresses the phosphorylation of Smad2/Smad3 [9,10]. Several lines of evidence demonstrated that TGF-β1 exerts strong suppressive functions on epidermal and mucosal inflammation [11,12]. Animals with impaired TGF-β1 signaling develop...

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IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis

Cited by 64 publications

References 43 publications

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

TGF‐β induces the differentiation of human CXCL13‐producing CD4⁺ T cells

Attenuated TGF‐β1 responsiveness of dendritic cells and their precursors in atopic dermatitis

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