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

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 beta-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.