Bacterial lipopolysaccharide induction of leukocyte-derived corticotropin and endorphins

Abstract

Previous reports have shown that there is an endogenous opioid component associated with pathophysiological responses to endotoxin. It has been shown that these responses are alleviated by naloxone, a specific opiate antagonist. Results of another study have indicated that leukocytes may mediate some of those responses since leukocyte depletion alleviated the effects of lipopolysaccharide. In view of the above reports as well as the finding that leukocytes produce immunoreactive (ir-) endorphins and corticotropin (ACTH) when stimulated with Newcastle disease virus or ACTH-releasing factor, we postulated that leukocytes may serve as an extrapituitary source of endorphins produced in response to bacterial endotoxin. To test this hypothesis, human peripheral blood leukocytes as well as mouse spleen cells were cultured in vitro with Escherichia coli lipopolysaccharide for 48 h. The lipopolysaccharide (i.e., endotoxin) was shown to induce de novo synthesis of ir-ACTH and ir-endorphins. The leukocyte-derived ir-ACTH had a molecular weight of approximately 2,900 and demonstrated a bioactivity similar to that of pituitary-derived ACTH. The lymphocyte-derived irendorphin comigrated with a-and y-endorphin at approximately 1,800 daltons and was shown to bind to brain opiate receptors. These findings imply that leukocyte-derived endorphins may be involved in the pathophysiological response to endotoxin.

β‐Endorphin: Cytokine and Neuropeptide

“…Data originally presented by Harbour et al (1987, Harbour-McMenamin et al 1985 indicated that processing of endorphins produced by the immune system can be different from processing pathways observed in the neuroendocrine system. Affinity chromatography and gel filtration of ir-ACTH derived from LPS-stimulated mouse splenocytes suggested production of ACTH 1-24 to 26.…”

“…Leukocyte-derived ACTH and endorphins are identical to their pituitary gland counterparts in terms of bioactivity, antigenicity, molecular weight and retention time on RP-HPLC. De novo synthesis was demonstrated by studying radiolabeled amino acid incorporation (Blalock & Smith 1985, Blaiock et al 1985, Harbour-McMenamin et al 1985. Harbour et al 1987.…”

“…Cells of the immune system, however, are not only capable of responding to neuropeptides, but also synthesize these substances. It has been shown by several authors that leukocytes produce and secrete peptide hormones such as endorphins, adrenocorticotropic hormone (ACTH), enkephalins, arginine-vasopressin (AVP), prolactin, thyroid-stimulating hormone, growth hormone and insulin-Hke growth factors (IGF) (Blalock et al 1985, Smith et al 1983, Zurawski et al 1986, Rosen et al 1989, Weigant & Blalock 1987, Kooiman et al 1990).…”

Functional histology of the neuroendocrine thymus

“…Stimulated immunocytes, including B and T lymphocytes, splenocytes, and monocytes produce factors that are immunologically and biologically, but not biochemically, identical to peptide hormones: ACTH, endorphin (END), TSH and hCG (Smith and Blalock, 1988). Interestingly, the leukocyte derived gene for the ACTH/ END precursor proopiomelanocortin (POMC) is identical, but the processing of POMC to its final peptide products differs somewhat from the pituitary (Harbour-McMenamin et al, 1985). Peripheral lymphocytic ACTH is steroidogenic , corticotropinreleasing factor (CRF) acts as inflammatory cytokine (Karalis et al, 1991), and lymphocytic endorphin binds to opiate receptors both in vivo and in vitro (Harbour-McMenamin et al, 1985).…”

Neuropeptide Regulation of Mucosal Immunity

“…lnterleukin-1 has also been shown to increase ACTH and corticosterone blood levels (Del Rey & Besedovsky 1987). Blalock and colleagues have further demonstrated the production of proopiomelanocortin-derived peptides (ACTH and 0 endorphin) by lipopolysaccharide-treated leukocytes (Harbour-McMenamin et al 1985), adding to tbe evidence for active involvement of immune cells in this circuit. Blalock has therefore suggested that the immune system can act as a sensory afferent organ for the central nervous system, surveying and discriminating between the constant onslaught of new molecules with which the body is faced , Carr & Blalock 1986.…”