Enkephalinase: A physiologic neuroimmunomodulator detected in the synovial fluid

Appelboom, Thierry; Maertelaer, Viviane De; Prez, Eric De; Hauzeur, Jean‐Philippe; Deschodt-Lanckman, M

doi:10.1002/art.1780340815

Cited by 20 publications

(7 citation statements)

References 11 publications

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“…In addition, the recent demonstration ofmeasurable NEP-24. 1 1 activity in synovial fluids (55) suggests that the synovial fibroblast, in addition to expressing NEP-24. 11 on its cell surface, may also have the capacity to secrete this enzyme into the joint cavity.…”

Section: Discussionmentioning

confidence: 99%

Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides.

Bathon¹,

Proud²,

Mizutani³

et al. 1992

J. Clin. Invest.

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Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue oftheir abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to (1.39±0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80±0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74±0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93±0.15 nmol/min per well) and DAP IV (0.84±0.18 nmol/ min per well) were responsible for the degradation of substance P. AmM (2.44±0.33 nmol /min per well) and NEP-24.11 (1.30±0.45 nmol / min per well) were responsible for the degradation of the opioid peptide, ILeu5lenkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint. (J. Clin. Invest. 1992. 90:981-991.)

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Section: Discussionmentioning

confidence: 99%

Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides.

Bathon¹,

Proud²,

Mizutani³

et al. 1992

J. Clin. Invest.

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“…The presence of the enzyme has also been reported in human neutrophils [7] where it may play a role in the regulation of inflammation and chemotaxis [8]. A soluble form of NEP has been found in human plasma, cerebrospinal fluid and amniotic fluid [9], and this activity has been reported to increase during inflammatory processes in the synovial fluid [10] and in the serum of patients with sarcoidosis [11] or with adult respiratory distress syndrome (ARDS) [12]. NEP was also reported to increase in the serum of patients with endstage renal failure [13], and its enhancement in urine seems to be a marker of proximal tubular injury [14].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a soluble form of neutral endopeptidase‐24.11 (EC 3.4.24.11) in human serum: enhancement of its activity in serum of underground miners exposed to coal dust particles

Soleilhac

Lafuma

Porcher

et al. 1996

Eur J Clin Investigation

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A previous epidemiological study has reported the elevation of a serum metalloendopeptidase activity for underground coalminers exposed to chronic inhalation of coal mine dust particles. In this work, we have unambiguously characterized this activity as neutral endopeptidase (EC 3.4.24.11) using five different criteria. The apparent molecular weight of 100,000 g mol-1 calculated for the serum peptidase using Western blots or direct binding of the neutral endopeptidase 24.11 inhibitor [125I]-RB104 to the enzyme in acrylamide gels, suggests that the soluble form of this ectoenzyme is not generated by a post-translational cleavage of the membrane-bound form, as is the case for the closely related ectoenzyme, angiotensin-converting enzyme. The circulating endopeptidase very likely results from a shedding process. The increase in serum neutral endopeptidase 24.11 activity of underground miners compared with surface miners (5.7-fold), P < 0.01) is not correlated with systemic inflammation parameters, but seems to reflect the chronic pulmonary inflammatory state induced by coalmine dust exposure, and so may be a marker of lung injury.

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“…This may result from either inhibition of their synthesis, or elevation of endopeptidase activity [7], as was demonstrated earlier in experiments with chronic administration of morphine [11]. On the other hand, it has been found that endopeptidase 24.11 can act as an immunomodulator [5] and its activation evidently not only accelerates proteolysis of opioids but also stimulates production of AMAB. Given the fact that AMAB bind with morphine more effectively than do morphine receptors [15], it may be assumed that stimulation of AMAB production is a key component in the formation of morphine resistance and tolerance.…”

Section: Resultsmentioning

confidence: 87%

Immunological correlation between morphine tolerance and the effect of naloxone in rats of different age

et al. 1996

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In 3-6-week-old morphine-sensitive rats, in which morphine injection produced an analgetic effect, the serum titer of antimorphine antibodies 24 h postinjection is less than half that observed in morphine-resistant animals. Administration of naloxone to morphine-sensitive rats induces hyperalgesia and considerably raises the serum titer of antimorphine antibodies. Chronic injections of the same dose of morphine, which cause its analgetic effect to disappear, increase the titer of antibodies in morphine-sensitive rats 2-fold. In morphineresistant rats naloxone produces an analgetic effect followed by its gradual decay and disappearance in the course of chronic administration. Subsequent administration of morphine induces analgesia, raises the titer of antimorphine antibodies, and lowers the titer of antiidiotypic antibodies. Key Words: morphine; tolerance; naloxone; antimorphine antibodies; antiidiotypesAlthough the immune system is known to play a role in the formation of morphine tolerance -the disappearance of the effect of the initial dose of the narcotic, which develops especially rapidly in children [13] -this role remains poorly understood [12]. It has been found that antimorphine antibodies (AMAB) are produced in animals and man in response to morphine injection [4]. However, there are morphine-resistant individuals [1,14], in whom the reactions of the immune system have remained virtually unstudied. Recently, special interest has been paid to the detection of not only idiotypic but also antiidiotypic antibodies [2], in particular AMAB (AIAMAB). However, so far there is no clear evidence that these antibodies play a part in the mechanisms of morphine tolerance.Moreover, administration of naloxone to morphine-resistant animals has been previously found to induce an analgetic rather than hyperalgetic (as in The aim of the present study was to investigate the dynamics of formation of AMAB and AIAMAB in 3-6-week-old rats with morphine resistance and in the course of tolerance development and naloxone treatment. MATERIALS AND METHODSThe experiments were carried out on 3-6-week-old male albino Wistar rats weighing 50-75 g. Changes in nociception were evaluated on an Ugo Basile automatic analgesimeter by the latency of the tail flick (LTF) in response to 10 presentations of a thermal nociceptive stimulus every 1.5-2 min (tail-flick test). The device switches off automatically after 40 sec to avoid skin burn.Morphine hydrochloride (2 mg/kg) and naloxone (0.3 mg/kg, Sigma) were injected subcutaneously and intraperitoneally, respectively.

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Enkephalinase: A physiologic neuroimmunomodulator detected in the synovial fluid

Cited by 20 publications

References 11 publications

Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides.

Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides.

Characterization of a soluble form of neutral endopeptidase‐24.11 (EC 3.4.24.11) in human serum: enhancement of its activity in serum of underground miners exposed to coal dust particles

Immunological correlation between morphine tolerance and the effect of naloxone in rats of different age

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