ABSTRACT
Neutral endopeptidase (NEP) 24.11 appears to be an important enzyme in both vertebrate and invertebrate autoimmunoregulation. Activation of human or invertebrate immunocytes that express NEP with substrates such as monokines and neuropeptides results in its increased expression, in other words, upregulation. However, since certain neuropeptides are also substrates for NEP, these activated immunocytes will respond to neuropeptides only at higher concentrations, thus downregulating the response. Specifically, in tumor necrosis factor (TNF)-treated immunocytes, we demonstrate the effects of increased NEP expression on altering the stimulatory activities of the neuropeptides met-enkephalin, melanocyte-stimulating hormone and substance P. We demonstrate the significance of NEP in modulating these responses through the use of specific enzyme inhibitors such as phosphoramidon, thiorphan and captopril. Furthermore, we present evidence suggesting that the individual variations seen in immunocytes from both different and the same donors to activating substances may reflect fluctuating levels of NEP expressed in response to endogenous stimuli. These results indicate that NEP is a highly significant factor in controlling the response(s) of certain immunocytes in man and higher invertebrates to the influence of biologically active substances such as monokines and neuropeptides.
Subject(s)
Autoimmunity/physiology , Neprilysin/biosynthesis , Neuropeptides/physiology , Tumor Necrosis Factor-alpha/physiology , Animals , Bivalvia , Dose-Response Relationship, Immunologic , Enkephalin, Methionine/pharmacology , Gene Expression Regulation/drug effects , Glycopeptides/pharmacology , Granulocytes/enzymology , Hemocytes/enzymology , Humans , In Vitro Techniques , Melanocyte-Stimulating Hormones/pharmacology , Neprilysin/antagonists & inhibitors , Substance P/pharmacology , Thiorphan/pharmacologyABSTRACT
1. Mytilus pedal ganglion contains a small population of glial cells that are immunopositive for interleukin-1 alpha. Positively stained fibers can also be seen in the neuropil of these sections. 2. The marine worm Nereis diversicolor also exhibits positive neural immunostaining for interleukin-1 alpha. 3. Both organisms contain hemocytes that contain immunoactivity for interleukin-1 alpha. The study suggests interleukin-1 alpha to be an ancient cytokine given its presence in organisms that evolved significantly earlier than mammals.
