Chaperonin 10 as a putative modulator of multiple Toll-like receptors for the treatment of inflammatory diseases

Abstract

Chaperonin 10 (Cpn10) is a mitochondrial protein that associates with chaperonin 60 (Cpn60) to form a multimeric molecular chaperonin complex whose main function is to promote the correct native folding of newly synthesized polypeptides within mitochondria. Cpn10 is also released extracellularly and can be found as an early pregnancy factor with immunomodulatory properties in the serum and urine of pregnant women. Furthermore, studies in animal models along with a recent clinical trial in rheumatoid arthritis patients have suggested that exogenously administered Cpn10 may hold potential for the treatment of inflammatory and autoimmune diseases. Investigations of the mechanism of immunosuppressive action of Cpn10 that focused on a possible functional modulation of the Toll-like receptor (TLR) system, known to play a central role in innate immunity and inflammation, have shown that Cpn10 can inhibit pro-inflammatory cytokine production mediated via TLR4 in macrophages. In these three patent applications by CBIO Ltd, the ability of Cpn10 to modulate TLR function is substantiated and extended to TLR2, TLR3, TLR6, TLR7 and TLR9. In addition, Cpn10-derived polypeptides that possess immunomodulatory activity, but little or no protein folding activity in the presence of Cpn60, are identified. Thirdly, it is shown that Cpn10 can ameliorate airway inflammation in a sheep model of asthma. Overall, these findings provide additional evidence that Cpn10 may participate in a novel pathway of immunoregulation. However, the exact molecular mechanisms involved in this pathway remain to be characterized. The efficacy and safety of Cpn10 as a therapeutic immunomodulator also need to be further defined.