The Protective Cytokine Hypothesis
TGF-beta acts on many cell types to maintain tissue homeostasis. In VSMCs TGF-beta promotes the expression of the proteins that compose the contractile apparatus, as well as inhibiting proliferation and migration (Biochem. J. 299:227). Furthermore, TGF-beta maintains the normal expression pattern of proteins on the endothelium, and is a well-established regulator of immune cell function. These observations lead us to propose the "Protective Cytokine Hypothesis" (Biol. Rev. 70:571 and more recently ATVB 24:399). This hypothesis states that:
"TGF-beta signaling is important for the maintenance of normal vessel wall architecture, and that loss of this protective signal is an important step in the development of atherosclerosis"
The protective cytokine hypothesis has gained weight as the evidence for the protective role of TGF-beta in atherosclerosis has accumulated. Furthermore, the hypothesis has been extended to encompass other chronic disease processes associated with aging that are typified with a progressive loss of the normal tissue structure and recruitment of leukocytes (such as atherosclerosis, osteoporosis, neurodegenerative diseases and cancer):
“The structures of many organs in the body are actively maintained, and TGF-beta participates in this maintenance (hence acting in a "protective" role). Loss of this protective signal is a common mechanism in heart disease, osteoporosis, Alzheimer’s Disease and other chronic diseases of the elderly."
A poster describing the evidence for the hypothesis was displayed at the House of Commons in 2000. We have only just begun to search for evidence of these common protective mechanisms in a wider range of diseases, but some encouraging results have already been found. For example, we found evidence for the presence of the TGF-beta3 isoform in serum from women with osteoporosis (Osteoporosis Int. 9:398). This isoform is not normally present in human blood, and we have suggested that its unexpected presence in osteoporosis may indicate a failure for its to be retained within the bone structure. Further extensions of this idea, such as the Load Coupling Hypothesis, have led us to propose that misregulation of TGF-beta activity might underlie the progressive symptoms of chronic heart failure and Duchenne Muscular Dystrophy. Although our investigations into these diseases are at an early stage, the results are encouraging. The presence of a unifying mechanism contributing to a wide range of chronic diseases provides some hope that improved preventative strategies might one day be available.
A model for the action of TGF-β1 on VSMCs during atherogenesis (ATVB 24:399).