DIURNAL RHYTHMICITY OF HUMAN CYTOKINE PRODUCTION - A DYNAMIC DISEQUILIBRIUM IN T-HELPER CELL-TYPE 1 T HELPER-CELL TYPE-2 BALANCE/

Diurnal rhythmicity is a characteristic of neuroendocrine pathways but is less understood in relation to immune function. We asked whether c ellular (type 1) or humoral (type 2) immune responses or type 1/type 2 balance exhibit diurnal rhythmicity in healthy humans, and, if so, wh ether this is related to plasma levels of cortisol or melatonin, two h ormones with immunomodulatory actions. LPS- or tetanus-stimulated huma n whole blood IFN-gamma and IL-10 production, and the IFN-gamma/IL10 r atio exhibited significant diurnal rhythmicity. The IFN-gamma/lL-10 ra tio peaked during the early morning and correlated negatively with pla sma cortisol and positively with plasma melatonin. IFN-gamma and, to a lesser extent, IL-10 production was sensitive to inhibition by exogen ous cortisone; the IFN-gamma/IL-10 ratio decreased by >70% after the a dministration of oral cortisone acetate (25 mg). Our findings support the concept that plasma cortisol and possibly melatonin regulate diurn al variation in the IFN-gamma/IL-10 ratio. As IFN-gamma and IL-10 have opposing effects on cellular immunity, changes in their balance would be anticipated to impose diurnal rhythmicity on cellular immunity. Th is implies that the nature of an immune response, e.g., to vaccination , may be modified by the time of day of Ag presentation and could be t herapeutically manipulated by the administration of cortisol or melato nin.