Elsevier

Pharmacology & Therapeutics

Volume 99, Issue 3, September 2003, Pages 327-338
Pharmacology & Therapeutics

The role of gp130/IL-6 cytokines in the development of pulmonary fibrosis: critical determinants of disease susceptibility and progression?

https://doi.org/10.1016/S0163-7258(03)00095-0Get rights and content

Abstract

Cryptogenic fibrosing alveolitis (CFA), also known as idiopathic pulmonary fibrosis (IPF), is the end stage of a heterogeneous group of disorders in which the deposition of excessive amounts of collagen results in the loss of lung function and premature death. The molecular mechanisms underlying the disease are unknown. Accordingly, there is much debate as to whether pulmonary fibrosis is the end result of (1) a chronic inflammatory process or (2) a disturbance in normal epithelium-fibroblast cross talk, or both. In addition, it appears increasingly likely that there is a genetic component in the development of pulmonary fibrosis. The IL-6 cytokine family is a group of pleiotropic mediators produced by a variety of cells in response to a inflammatory stimuli. These cytokines are grouped together on the basis of weak structural homology, overlapping functions, and shared use of the transmembrane glycoprotein β-subunit gp130 as part of their multimeric receptor complexes. Activation of these receptor complexes results in the recruitment and phosphorylation of specific transcription factors. In addition, membrane-proximal tyrosine residues act as docking sites for molecules involved in the activation of extracellular signal-related kinase (ERK). However, studies in genetically engineered mice that overexpress members of this family have shown that while overlapping biological activities exist, there are effects specific to individual cytokines. Data from both human and animal studies are now emerging to suggest that members of this cytokine family play an important role in the pathogenesis of fibroproliferative diseases and thus represent a novel group of cytokines implicated in pulmonary fibrosis. Importantly, manipulation of signaling pathways activated by these cytokines may suppress fibrosis but leave innate cellular mechanisms necessary for host defense largely untouched. This may provide guides for the development of novel pharmacological treatment for fibroproliferative diseases.

Introduction

Fibrosis can be defined as an excessive deposition of extracellular matrix components that results in the destruction of normal tissue architecture and a compromise in tissue function. If fibrosis occurs in the major organs such as lung, it will inevitably lead to organ failure and death of the individual.

The development of fibrosis appears to follow a similar pathway to that of normal wound healing; however, in most cases, there is a chronic progression of the disease without resolution. Clearly, the normal fine control of cell function that occurs during normal healing is disturbed. Current therapies for fibrosis aim to inhibit inflammation, but this is effective in only a small subset of patients. There are currently no proven therapies targeting the fibrotic response itself. A significant research effort is being directed towards establishing the relative roles of growth factors and cytokines that may determine the pathogenesis and outcomes of the disease. Support for this strategy is derived from a joint statement produced by the American Thoracic and European Respiratory Societies in which the roles of various growth factors and cytokines were described as “critical” to the process of fibrosis.

The interleukin (IL)-6/gp130 family of cytokines has the potential to exert endocrine, autocrine, and paracrine effects within the lung and therefore regulate local inflammatory and subsequent healing events. The aim of this manuscript is to review current knowledge on the role that cytokines, which signal through gp130, play in the susceptibility to and progression of pulmonary fibrosis.

Section snippets

The gp130/interleukin-6 family of cytokines

The IL-6 family of cytokines is a group of related pleiotropic acting cytokines that are produced by a variety of cells in response to inflammatory stimuli Kishimoto et al., 1995, Heinrich et al., 1998. Individual family members play pivotal roles in the immune, nervous, cardiovascular, and hemopoietic systems as well as bone metabolism, inflammation, wound repair, acute phase response, and development of the embryo Hirota et al., 1995, Hirano et al., 1997, Taga, 1997, Betz et al., 1998. The

gp130-dependent intracellular signal transduction pathways

Following ligand-mediated gp130 homodimerization or heterodimerization, juxtapositioning of the cytoplasmic Janus kinases (JAK), which are constitutively associated with the receptor β-chains, results in activation and subsequent phosphorylation of highly conserved cytoplasmic tyrosine residues in gp130, LIFRβ, and OSMRβ (Heinrich et al., 1998). Although gp130 associates with and leads to activation of Jak1, Jak2, and Tyk2, knockout studies suggest that in most cell types Jak1 is the critical

The suppressor of cytokine signaling family of proteins

One of the key factors involved in the negative regulation of gp130 signaling is the family of suppressor of cytokine signaling (SOCS) proteins (Starr & Hilton, 1999). Generally, individual SOCS genes are transcriptionally activated in response to cytokine stimulation, often via STAT-mediated mechanisms, to inhibit cytokine signaling via a classical negative feedback loop. The SOCS proteins inhibit phosphorylation of receptors and their associated intermediate signaling proteins (i.e., STAT) by

Cryptogenic fibrosing alveolitis

Cryptogenic fibrosing alveolitis (CFA), also known as idiopathic pulmonary fibrosis (IPF), is a specific form of chronic diffuse interstitial lung disease of unknown etiology (American Thoracic Society, 2000). The disease is confined to the lung and is characterized pathologically by areas of inflammation and excessive deposition of extracellular matrix (ECM) in the lung parenchyma King et al., 2001, Selman et al., 2001. The disease occurs predominantly from middle age onwards, with two-thirds

The central role of the myofibroblast in cryptogenic fibrosing alveolitis

Fibroblastic foci are generally located with the interstitial space directly beneath the alveolar epithelium often at the boundary of areas of collagen deposition and normal appearing lung Bjoraker et al., 1998, Mason et al., 1999. These foci are characterized by fibroblast/myofibroblast accumulation through proliferation and decreased apoptosis as well as enhanced release of and response to profibrotic growth factors. At these sites, there is impaired reepithelialization and inappropriate

Current therapeutic strategies used in cryptogenic fibrosing alveolitis

Initial hypotheses on the progression of CFA involved the accumulation of inflammatory and immune cells around the damaged lung parenchymal tissue, and as such, conventional treatment of CFA has been based on inhibiting inflammation and inducing immunosuppression. However, aggressive treatment regimens using corticosteroids and immunosuppressive or cytotoxic agents are only useful in a small percentage of patients with CFA. In the majority of cases, the disease remains progressive and

Interleukin-6

IL-6 has a variety of well-documented direct effects that are potentially relevant to inflammation and remodeling, although its potential role in fibrosis is largely unknown. IL-6 is released following stimulation by profibrogenic growth factors such as TGFβ Eickelberg et al., 1999a, Eickelberg et al., 1999b and may even mediate some cellular effects attributable to these molecules (Roth et al., 1995). IL-6 has been shown to stimulate dermal fibroblasts to produce collagen, and enhanced

Investigation with genetically engineered mice suggest that cytokines that signal through gp130 are important in fibrosis

The use of genetically engineered mice that overexpress IL-6 cytokines show that while they share overlapping biological activities there are also distinct effects specific to each cytokine.

Evidence for a genetic component in cryptogenic fibrosing alveolitis

It appears increasingly likely that there is a genetic predisposition to CFA. This hypothesis is supported by the existence of familial forms of the disease Marshall et al., 1997, Marshall et al., 2000. In addition, there is often marked variation in the fibrotic response observed between individuals exposed to particulates and chemotherapeutic agents, such as asbestos and bleomycin, despite similar levels of exposure.

The pattern of inheritance is not certain but appears to be autosomal

Genetic influences in interleukin-6/gp130 cytokine signaling in cryptogenic fibrosing alveolitis

Although IL-6 may promote fibrogenesis and levels of IL-6 are markedly increased in BAL fluid from patients with CFA compared with sarcoidosis (Shahar et al., 1996), a genetic component to the role of IL-6/gp130 cytokines in the pathogenesis of CFA remains largely unexplored. However, genetic studies in mice have shown strong association between IL-6 and the development of fibrosis (Baecher-Allan & Barth, 1993). Perhaps more convincingly, in a study of 74 patients, analysis of TNFα, TNFα

Summary and future directions

Current thinking suggests that the pathogenesis of CFA involves an influx of inflammatory and immune cells, which, together with activated resident cells, release mediators to induce fibroblasts to proliferate and produce excess collagen. However, it remains unclear why a particular insult results in an ongoing fibrotic response rather than self-limiting wound healing. Current therapies to treat CFA aim to inhibit inflammation, but this is effective in only a small subset of patients. Under

Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia. YM is a recipient of the SAPS/3M respiratory fellowship.

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