IL-11 Is a Therapeutic Target in Idiopathic Pulmonary Fibrosis

Cook, Stuart A.; Ng, Benjamin; Dong, Jinqiao; Sivakumar, V.; D’Agostino, G.; Widjaja, Anissa A.; Lim, Wei‐Wen; Ko, Nicole S. J.; Tan, Jessie; Chothani, Sonia; Huang, Brady K.; Xie, Chen; Chacko, Ann‐Marie; Guimarães-Camboa, Nuno; Evans, Sylvia M.; Byrne, Adam; Maher, TM; Liang, Jiurong; Noble, Paul W.; Schäfer, Sebastian

doi:10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a1234

Cited by 7 publications

(47 citation statements)

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“…Thum et al have shown that in pressure overloaded mouse heart microRNA-21 stimulates the ERK-MAP kinase signaling pathway in cardiac fibroblasts and contributes to disease pathogenesis. 36 Moreover, recent studies from Ng et al group have demonstrated that in response to a pro-fibrotic stimulus, IL-11 regulates fibrogenic protein synthesis via ERK signaling 16 However, there are very few reports on GSK-3 and ERK interaction. An elegant study from Ding et al group demonstrated a critical role of ERK in priming and inactivation of GSK-3β in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, IL-11 is demonstrated to act via an autocrine manner and is shown to cooperate with the ERK pathway to mediate fibrotic response in FBs. 16 Hence, we examined the effect of GSK-3α deletion on IL-11 levels in CFs. Interestingly, our flow cytometric analysis results revealed a significant reduction in IL-11 +ve CFs in KO as .…”

Section: Effect Of Cf-gsk-3α Deletion On Il-11 and Erk Pathwaymentioning

confidence: 99%

“…10 A recent study has shown that TGF β 1 increases IL-11 expression in fibroblast which in turn regulates translation of fibrogenic proteins via non-canonical, ERK-dependent pathway. 16 All these studies indicate that multiple distinct pathways cooperate with classical TGF β signaling in fibroblast to mediate fibrotic response in the diseased heart.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac fibroblast GSK-3α mediates adverse myocardial fibrosis via IL-11 and ERK pathway

Umbarkar¹,

Tousif²,

Ap³

et al. 2021

Preprint

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Background: Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK-3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in myocardial fibrosis is unknown. Methods and Results: Herein, we employed two entirely novel conditional fibroblast-specific and tamoxifen-inducible mouse models to define the role of CF-GSK-3α in fibroblast activation and myocardial fibrosis. Specifically, GSK-3α was deleted from cardiac fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin-promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury, and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In both settings, GSK-3α deletion restricted fibrotic remodeling and improved cardiac function. To investigate underlying mechanisms, we examined the effect of GSK-3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro. A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1 treated GSK-3α KO MEFs confirmed that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK-3α is SMAD3 independent. To further delineate the underlying mechanism, total proteins were isolated from CFs of WT and KO animals at 4 weeks post-injury, and kinome profiling was performed by utilizing PamStation12 high throughput microarray platform. The kinome analysis identified the downregulation of RAF family kinase activity in GSK3α-KO-CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Importantly, flow cytometric analysis of CFs confirmed a significant decrease in pERK levels in KO mice. Additionally, our in vitro studies demonstrated that GSK-3α deletion prevented TGFβ1 induced ERK activation thereby validating our findings from kinome analysis. Interestingly, IL-11, a fibroblast specific downstream effector of TGFβ1, was very low in GSK-3α KO MEFs as compared to WT and ERK inhibition further reduced IL-11 expression in them. All these results indicate that GSK-3α mediates pro-fibrotic response in the injured heart through IL-11 and ERK pathway. Conclusion: CF-GSK-3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Cf-gsk-3α Deletion On Il-11 and Erk Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cardiac fibroblast GSK-3α mediates adverse myocardial fibrosis via IL-11 and ERK pathway

Umbarkar¹,

Tousif²,

Ap³

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…IL-11 has been implicated in fibrosis of the heart ( 212 ), liver ( 213 ), and lung ( 214 , 215 ). Fibrosis is the generation of excess connective tissue, and is a hallmark of several diseases, including late-stage cardiovascular disease, and liver diseases such as non-alcoholic liver disease.…”

Section: Biological Roles Of Il-11mentioning

confidence: 99%

“…Antibodies against IL-11 ( 214 , 309 ) and IL-11Rα ( 213 , 310 , 311 ) that inhibit IL-11 signaling have been described and patented, although none are clinically available. The mechanisms of action of these antibodies have not been described in the literature.…”

Section: Therapeutic Targeting Of Il-6 Family Cytokine Signalingmentioning

confidence: 99%

Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11

2020

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Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling.

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