STAT3 in tissue fibrosis: Is there a role in the lung?

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Abstract

Fibrosis is defined as an excessive deposition of connective tissue components that results in the destruction of normal tissue architecture and compromises organ function. When fibrosis occurs in the major organs such as the lung, for example in idiopathic pulmonary fibrosis, it inevitably leads to organ failure and premature death of the afflicted individual. Current evidence suggests that fibrosis initially develops along the same pathway as normal wound healing, although there is chronic progression of the disease without resolution, suggesting the control of intracellular processes that occur during wound healing is disturbed. It follows then that determining where this control is lost is key to preventing and treating this condition. The IL-6 cytokine family is a group of pleiotropic cytokines produced by a variety of cells in response to inflammatory stimuli. These cytokines are grouped together on the basis of overlapping functions, and common usage of gp130 as part of their multimeric receptor complexes. Activation of these receptor complexes results in the recruitment and phosphorylation of the latent transcription factor STAT-3 which induces a gene program involved in cell differentiation and proliferation. STAT3 also induces expression of a number of inhibitors including SOCS-3. In this manuscript we review the available literature on the IL-6/gp-130 family of cytokines and their role in regulating fibrosis. Despite a large number of studies in mouse models as well as human cells in vitro, the role of these cytokines or STAT3 activated by other cytokines in the development of fibrosis remains unclear.

Section snippets

STAT3

STAT3 is a latent cytoplasmic transcription factor that plays critical roles in several biological pathways crucial to cell function, including proliferation, migration, survival, and differentiation [1].

STAT3 exists in two isoforms generated by alternative splicing of a common gene; the full length STAT3α (86–92 kDa) and the truncated STAT3β (79–82 kDa) which lacks the C-terminal activation domain and is generally thought to act as a dominant negative factor [2], [3], [4]. STAT3β lacks the

Activation of STAT3

The predominant receptors coupled to STAT3 signaling are the gp130/interleukin-6 (IL-6) receptor family, although Receptor Tyrosine Kinase (RTK) and IL-10R signaling may also induce STAT3 activation.

Other activation pathways

We have recently shown that endothelin-1 receptors can also induce phosphorylation of STAT3, most likely through intracellular cross-talk [14]. Some non-receptor tyrosine kinases such as the Src family (Lck in particular) may also directly activate STAT3 in the absence of a classical stimulus [15]. In addition to Tyr705 phosphorylation, STAT3 is also phosphorylated at Ser727. Several recent studies have suggested that Ser727 phosphorylation is required for nuclear translocation and maximal

The SOCS-family

One of the key factors involved in the negative regulation of gp130 and STAT signaling is the family of Suppressor of Cytokine Signaling (SOCS) proteins. The family of 8 structurally related proteins are produced as a result of cytokine stimulation and subsequent STAT-mediated gene transcription [17], [18], [19], [20]. Once expressed, the SOCS proteins inhibit STAT phosphorylation and signal transduction by at least two distinct mechanisms. SOCS proteins can interact with the catalytic domains

Is there a role for STAT3 in fibrosis – evidence from other organs

While the specific role of STAT3 in fibrosis remains unclear, studies in liver, skin and kidney all point towards a regulatory role for STAT3 in the pathogenesis of fibrosis. However, these studies are contradictory with the results of some arguing for a protective role and others a pro-fibrotic role for STAT3. CCl4-induced liver fibrosis is increased in IL-6 deficient mice [28]. Furthermore, using the Cre–loxP system Streetz et al. knocked out gp130 signaling in hepatocytes (AlfpCre) or

Idiopathic pulmonary fibrosis (IPF)

IPF/usual interstitial pneumonia (UIP) is a term that describes a chronic fibrosing interstitial pneumonia of unknown aetiology. IPF/UIP is the most common of interstitial pneumonias and is also the most unresponsive to current therapies [35]. Current epidemiological studies suggest that IPF is more common in male subjects, with onset in middle age. There are no distinct geographic, racial or ethnic group distributions of the disease. Although the precise aetiology is unknown, a number of risk

IL-11

IL-11 is released in large amounts from fibroblasts, epithelial cells and infiltrating macrophages. Overexpression of IL-11 in the lung produces peri-bronchiolar mononuclear cell infiltrates. Interestingly, in contrast to IL-6, overexpression of IL-11 induces collagen deposition, suggesting that IL-11 may play a central role in developing fibrosis [49]. More recently, IL-11 was shown to be involved in a positive feedback loop with TGFβ, further amplifying its pro-fibrotic potential [50].

OSM

OSM is

Is there genetic evidence for the IL-6/STAT3 cytokines in IPF?

There is increasing evidence to support a genetic predisposition to IPF [73], [74], [75]. Studies assessing the contribution or association of IL-6/gp130 cytokines to lung disease and IPF in particular are scarce. Pantelidis and colleagues have shown that an intronic polymorphism in the IL-6 gene is independently associated with IPF [76]. The significance of an intronic polymorphism is not clear, although the polymorphism has a strong association with a promoter polymorphism associated with

Summary

In summary, STAT3 has the capacity to be activated by a broad spectrum of upstream tyrosine kinase activities and in this capacity it has been identified as a promising target for cancer therapy. The idea that STAT3 may contribute to the progression of lung fibrosis is intriguing and is supported by several indirect observations. Hyperactivation of gp130 through increased cytokine levels or genetic mutations is one mechanism that may lead to STAT3 regulation of fibrosis, however other

Funding

This work was supported by the British Columbia Lung Association, Canadian Institutes for Health Research (MOP97993), the Wolfe and Gita Churg Foundation, Australian National Health and Medical Research Council (458703) and the Rashpal Dhillon Fund for IPF Research. DAK is the Canada Research Chair in Airway Disease and a Michael Smith Foundation for Health Research Senior Scholar. CMP is currently funded by a Heald Fellowship from Arthritis Australia.

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      Citation Excerpt :

      Finally, interstitial lung disease (ILD) represents another example of an aspect of STAT3 GOF disease that may not only be immune cell related [17,26]. STAT3 is involved in the extracellular matrix remodeling mechanism during wound healing responses of fibroblasts [76,77] and has been implicated in mediating pulmonary fibrosis [78–82]. The crucial role of STAT3 signaling in fibrotic transformation together with the increased susceptibility to infections may explain the severe pulmonary manifestations observed in some STAT3 GOF patients (Gothe et al., submitted).

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      Specifically, in fibrogenesis, IL-6 and CD44 promote the phosphorylation of STAT3 and its translocation to nucleus for further gene transcription. Additionally, STAT3 controls crosstalk between epithelial cells and fibroblasts which in turn contributes to disease progression (Knight et al., 2011; Chakraborty et al., 2017). Polyphenols are secondary metabolites from plants usually bearing high antioxidant properties and nutrient values.

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