Final Activity Report Summary - SISI (Stress-Immune Systems interactions) Stress is a scientific concept, which has suffered the mixed blessing of being too well known and too little understood. Importantly, stress represents one of the major health problems in industrialised countries, influencing the quality of life and well-being of the European citizens. Epidemiologic studies have linked acute or chronic stress with the development of several common human diseases such as infections, allergy, autoimmunity, atherosclerosis and cancer. However, the precise mechanisms of how stress may increase the susceptibility to, or the activity and severity of these diseases remain poorly understood. In our study and in projects supported by the Marie Curie International Reintegration Grant (IRG), we obtained the following results: 1) stress hormones, such as glucocorticoids and catecholamines exert systemically a potent inhibitory effect on the production of human interleukin (IL)-23; 2) human carotid atherosclerotic lesions (plaques) express high levels of IL-23; 3) human neuropeptide Y (NPY), a major stress hormone and mediator of chronic stress induces potent chemotactic responses in human dendritic cells (DCs, major effector and regulatory immune cells) and promotes a significant trans-endothelial migration of these immune cells. Cytokines represent chemical messengers between immune cells, or hormones of the immune system, which play crucial roles in mediating and controlling inflammatory and immune responses. IL-23 is a new, recently described cytokine, critically involved in mediating inflammatory and autoimmune processes, and promoting tumour incidence and growth. IL-23 also stimulates a novel family of CD4+ T helper (Th) immune cells, characterised by IL-17 production and named 'Th17' cells. It is already known that stress hormones mediate immunosuppression, more specifically of the cellular immunity, through selective inhibition of the Th1 cells axis, and its relevant cytokines. Thus, our study reveals a new, additional mechanism of immunosuppression mediated by stress hormones - through inhibition of the IL-23?Th17 axis. Our results suggests that excessive systemic levels of stress hormones, achieved during an acute or chronic stress, through an inhibition of the Th1 and IL-23?Th17 axis, and thus, suppression of cellular immunity, may contribute to the pathogenesis of several human infections, where cellular immunity has protective effects. On the other hand, a hypoactive stress system, and thus a deficiency of endogenous stress hormones that may occur in some autoimmune diseases such as rheumatoid arthritis or multiple sclerosis, may contribute to the prevalence of 'hyperactive' Th1 and IL-23?Th17 axis pro-inflammatory responses, and thus, to the pathogenesis of these serious and chronic human disorders. In addition, our results might be also relevant to the complex hormonal-cytokine interactions in local inflammatory and immune responses implicated in the pathogenesis of chronic conditions such as allergy, atherosclerosis, systemic lupus erythematosus, psoriasis and tumour incidence and growth. Our study also documents for the first time the involvement of IL-23 in human atherosclerosis, a significant finding that may have important fundamental, clinical and pharmacological implications. In addition, our study suggests that NPY, which levels are increased during chronic psychological stress, could act as an early pro-inflammatory signal by the recruitment of DCs at the site of inflammation, a process that may play an important role in the pathogenesis of atherosclerosis and / or some inflammatory / autoimmune conditions.
