| dc.description.abstract | The stress response enzyme, Heme Oxygenase 1 (HO-1), has been identified as an important immunomodulator which is highly upregulated in response to cellular stress and inflammation. HO-1 catalyses the conversion of free heme into the linear tetrapyrroles (LTPs), biliverdin (BV) and bilirubin, with the concomitant release of carbon monoxide. Interestingly, HO-1 and its reaction products have been reported to be protective in various models of autoimmune and inflammatory disease. Despite the promising therapeutic potential of the HO-1 system, implementation of HO-1-based therapies is hindered by the lack of clinically suitable HO-1 inducers and products. The plant-derived polyphenols, carnosol and curcumin, have been identified as candidate HO-1 inducers, however, there has been limited investigation into their effects on human immune cells. Furthermore, the marine-derived LTP, phycocyanobilin (PCB), is a structural analogue to BV, yet their anti-inflammatory activities have not been directly compared.
In order to determine whether carnosol, curcumin and PCB are viable alternatives to currently-available HO-1 modulators, and to learn more about the HO-1 system in general, this study investigated their effects on the immunologic and metabolic functions of human dendritic cells (DC) and peripheral blood mononuclear cells (PBMC). The results demonstrate that carnosol and curcumin effectively regulate the maturation and pro-inflammatory functions of human DC, through HO-1 dependent inhibition of mitogen-activated protein kinase signalling. Additionally, PCB was found to display similar efficacy to BV as an immunomodulator in human DC, and both BV and carbon monoxide were identified as important mediators of HO-1 anti-inflammatory activity in DC. Carnosol and curcumin also regulated the metabolic reprogramming of activated DC and PBMC, and a novel signalling pathway involving AMP-activated Protein Kinase-dependent upregulation of HO-1 by these polyphenols was uncovered in the course of this study. Treatment of PBMC and CD4+ T cells with carnosol or curcumin was additionally found to significantly reduce T cell proliferation and pro-inflammatory cytokine production. Finally, the anti-inflammatory effects of these polyphenols observed in healthy human PBMC was applied to the context of psoriasis through investigation of their efficacy in ex vivo psoriasis patient PBMC. Curcumin, but not carnosol, significantly inhibited T cell proliferation and cytokine poly-functionality, with reduced expression of the psoriasis-associated cytokines IFNγ, IL-17, GM-CSF and IL-22 observed in curcumin-treated PBMC. These results therefore describe the immunological effects of carnosol, curcumin and PCB in human immune cells, and, furthermore, provide important insight into the mechanism of action of HO-1 in human DC, and its relationship to immunometabolism. Thus, this study supports the use of these naturally-derived compounds as alternative modulators of the HO-1 system, with relevance for the treatment of autoimmune and inflammatory diseases. | en |
