Clinical Pharmacology & Biopharmaceutics
Open Access

Abstract

It has been well established that the immune and neuroendocrine systems interact and communicate with each other. We have demonstrated that methionine-enkephalin (Tyr-Gly-Gly-Phe-Met [YGGFM]) and certain of its peptide derivatives (Tyr-Gly-Gly [YGG] and Tyr-Gly [YG]) modulate immune responses in a biphasic manner with suppression at high doses and enhancement at low concentrations. These data showed in vivo (via DTH responses) and in vitro (via cytokine production) that met-enkephalin, YGG and YG modulated immune responses in a concentration-dependent biphasic manner without affecting the overall number of cells. The di- and tri-peptides showed a higher specific activity than the parent molecule with YG being the smallest active moiety. Tyr alone and GGFM were both inactive. Although YG and YGG were more potent than met-enkephalin in immune enhancement, an analog of met-enkephalin resistant to peptidase activity [DADME] enhanced responses but did not induce suppression. Thus, while cleavage of YGGFM to YG may be required for suppression it is not required for immune enhancement. Naloxone (an opioid receptor antagonist) blocked enhancive but not suppressive effects of met-enkephalin. Thus, binding to classical opiate receptors may be involved in the initiation of enhancement by met-enkephalin while cleavage to YG and an unidentified, nonopioid receptor may be associated with suppression. This is consistent with negative feedback such that when the concentration of YG increases, a suppressor mechanism downregulates the response. Thus, these studies may identify a novel mechanism heretofore unrecognized and given that the enkephalins are conserved throughout nature, it may represent one of the oldest means of regulating immune responses in phylogeny.

Biography

Email: sizemore@alcorn.edu