Transforming growth factor β1 (TGFβ1) is known to be an important profibrotic factor directly acting on fibroblasts. TGFβ1 induces migration of fibroblasts and promotes growth, activation, and collagen synthesis.1 However, TGFβ is not an ideal target because it acts on many cell types and has pleiotropic effects including the control of inflammation and regulatory T-cell function.2,3 In their recent publication in “Nature,” S. Schafer and coworkers identified downstream targets of TGFβ in fibroblasts aiming to effectively interfere with the profibrotic effects of TGFβ.4 The authors performed gene expression analysis (RNA-seq) on unstimulated and TGFβ stimulated primary human cardiac fibroblasts and found that interleukin (IL)-11 (both, mRNA and protein) are highly upregulated by TGFβ. Only a minor expression of IL-11 was detected in other tissues or cell types. Subsequently the authors found that a large variety of other profibrotic stimuli including platelet-derived growth factor, connective tissue growth factor, basic fibroblast growth factor, and IL-13, also induced IL-11 protein expression. Of note, the IL-11 receptor alpha chain is highly expressed on fibroblasts and to a lower degree on osteoblasts, adipocytes, melanocytes, and mesenchymal stem cells.
…’S. Schafer and coworkers identified downstream targets of TGFβ in fibroblasts aiming to effectively interfere with the profibrotic effects of TGFβ.
IL-11 is a member of the IL-6 family of cytokines. The IL-11 receptor has similarities to other members of the IL-6 family of receptors and is composed of an IL-11–specific receptor alpha-chain that binds IL-11 and the GP130 subunit, the common receptor beta-chain subunit that functions as the signal transduction component of this receptor family.5
In vitro characterization of human and mouse fibroblasts revealed that IL-11 (as TGFβ) promotes growth of myofibroblasts and increases their motility, contraction, invasion, and matrix production. Moreover, the effects of TGFβ and other profibrotic factors on fibroblasts were dependent on IL-11. However, in contrast to TGFβ, the profibrotic effects of IL-11 on fibroblasts were almost invisible on mRNA levels. Instead of a transcriptional regulation, IL-11 is operative on a posttranscriptional level using ERK-signaling pathways that activate fibroblasts. ERK-pathways are also used by other profibrotic factors and may thus be coamplified by IL-11.
IL-11 not only binds to membrane-bound but also to soluble (shed) forms of the IL-11 receptor alpha chain. This ligand-receptor complex can bind and activate cells expressing the common signal-transducing receptor beta chain GP130 (in trans signaling). Other members of the same cytokine family (eg, IL-6) can also activate cells by in trans signaling. IL-6 in trans signaling, in turn, has been shown to hyperactivate TGFβ pathways while inducing fibrosis via release of profibrotic gremlin.6 In addition, IL-6 promotes fibrosis by downregulating matrix metalloprotease activity and reducing matrix degradation.7,8 It remains unclear if IL-11 and IL-6 use similar profibrotic pathways (Figure 1).
The authors showed that IL-11 is upregulated in hearts of mice with cardiac fibrosis and preferentially expressed by fibroblasts with transcriptional features of TGFβ stimulation. In a mouse model of myocardial infarction, injection of recombinant mouse IL-11 stimulated fibroblasts in the epicardium causing ventricular impairment. Injection or transgenic overexpression of IL-11 in healthy mice induced collagen expression in fibroblasts of the epicardium and renal interstitium accompanied by a reduction in cardiac and renal function. Inhibition of IL-11 signaling was then analyzed in IL-11 receptor alpha knockout mice. These mice developed significantly less fibrosis in 2 models of cardiac fibrosis (angiotensin II infusion and transverse aortic constriction) and a model of renal fibrosis (folate induced kidney damage).
In summary, the data by Schafer and others indicate that expression of IL-11 is effective downstream of various profibrotic factors, including TGFβ. IL-11 promotes growth, activation, and collagen synthesis of fibroblasts in a posttranscriptional manner involving ERK signaling. The known upregulation of IL-11 in human fibrotic diseases (idiopathic pulmonary fibrosis and systemic sclerosis)9 together with the efficacy data in preclinical animal models suggest that IL-11 may serve as a potential therapeutic target to mitigate fibrosis.
Further studies will be required to determine whether reduction of fibrosis will improve organ function.10 Moreover, it will be interesting to identify appropriate diseases and conditions for an anti-IL-11–based antifibrotic therapy.
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