Enhancement by clofazimine and inhibition by dapsone of production of prostaglandin E2 by human polymorphonuclear leukocytes in vitro

Abstract

The effects of the antileprosy agents clofazimine and dapsone (1 to 10 ,ig/mi) on the spontaneous and stimulated release of prostaglandin E2 (PG E2) by human polymorphonuclear leukocytes (PMNL) in vitro have been investigated. PMNL were obtained from normal adult volunteers and three patients with leprosy (two borderline lepromatous and one subpolar lepromatous leprosy). The synthetic chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) at a concentration of 10-7 M was used as the stimulant of PG E2 synthesis. None of the test agents at the concentrations used inhibited the binding of radiolabeled FMLP to PMNL. However, dapsone at 5 and 10 ,ug/ml inhibited the spontaneous and FMLP-induced release of PG E2 by PMNL. Clofazimine, on the other hand, significantly Increased both the spontaneous and the FMLP-induced synthesis of PG E2 by PMNL. The enhancing effects of clofazimine on FMLP-mediated synthesis of PG E2 were particularly striking and were observed at concentrations of 1 to 10 jig of the drug per ml. Measurements of PMNL spontaneous and FMLP-induced synthesis of PG E2 in the presence of both clofazimine and dapsone (5 ,ug/ml) indicated that the two drugs are mutually antagonistic. PMNL from both normal control subjects and patients with leprosy were equally sensitive to these effects of clofazimine and dapsone. The immunostimulatory and immunosuppressive properties of dapsone and clofazimine, respectively, may be related to the opposite effects of these agents on PG E2 synthesis in human leukocytes.

Effects of Anti-Tuberculosis Drugs on the Production of Prostaglandin E₂ and on Mononuclear Leucocyte Transformation

“…However, in this study only RMP at approximately 10 times ther apeutic concentrations showed a stimula-tory effect on the production of PGE2 by PMNL, whereas none of the other com pounds had any statistically significant ef fects at the concentrations investigated. The negative finding for RMP at 25 ¡ig/m\ is consistent with previous results where no effect on the PGE2 synthesis was ob served at 10/rg/ml [8]. Strickland and Mitchell [15] investigated the effect of SM at the concentrations 2, 20 and 200 /zg/ml on the synthesis of PGEi and PGF2" using arachidonate and a microsome-enriched preparation of bovine seminal vesicle PG synthase.…”

“…Two agents with antimycobacterial activity have been described which increase and decrease re spectively the synthesis of PGE2 by PMNL in vitro, viz. clofazimine and dapsone [8]. Of the 5 anti-TB drugs investigated in the present study 3 have been reported to possess immunomodulatory properties, namely RMP, INH and SM [9][10][11][12][13][14] and it seemed possible that these properties could be mediated by modulation of the synthesis of PGs.…”

HLA expression in hepatocellular carcinoma cell lines

“…also known as lamprene or B663, is an effective anti-leprosy agent [13.14,37] with antiinflammatory and immunosuppressive properties [38][39][40] that stimulates the phagocytic and microbicidal activities [15] of human and murine phagocytes [38][39][40] by potentiating thc activity of lysosomal enzymes [16,41]. The increased intracellular killing abiHty of phagocytes in the presence of clofazimine has been suggested to be due to its priming effects on phagocytes [17].…”

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

“…In addition, PLA 2 activation and lysophosphotidylcholine accumulation have been held responsible for inhibition of the membrane Na ϩ ,K ϩ -ATPase, a key enzyme in various lymphocyte functions (15). Cyclosporine was shown to potentiate the immunosuppressive activity of clofazimine through a PLA 2 -Na ϩ ,K ϩ -ATPase-dependent mechanism (305); other immunosuppressive and anti-inflammatory effects of clofazimine could be related to its ability to scavenge chlorinating oxidants (see above) and to stimulate prostaglandin E 2 production by neutrophils (12).…”