Novel sulfhydryl-reactive compounds orazipone and OR-1958 inhibit cytokine production and histamine release in rat and human mast cells.
Orazipone (OR-1384) and OR-1958 are novel anti-inflammatory sulfhydryl reactive compounds with potential applications in the treatment of chronic obstructive lung disease and colitis. Mast cells are potent immune system cells which can be found in abundant numbers in mucosa of lung and gut. We have studied whether the anti-inflammatory effect of these compounds could be mediated through inhibition of the function of mast cells and compared their effects with the glucocorticoid budesonide. Human mast cell line (HMC-1) cells were activated using a combination of a calcium ionophore and a phorbol ester and the production of cytokines was measured using ELISA assay. Tumour necrosis factor-alpha mRNA levels were assessed using a semiquantitative reverse transcriptase polymerase chain reaction assay. Histamine release was studied in rat peritoneal mast cells. Orazipone, OR-1958 and budesonide inhibited significantly and dose dependently tumour necrosis factor-alpha production in HMC-1 cells with IC50-values of 20, 10, and 0.25 microM, respectively. Polymerase chain reaction studies showed that OR-1958 attenuated the activation-induced increase of tumour necrosis factor-alpha mRNA in HMC-1 cells. OR-1958 and, to a lesser extent, orazipone inhibited dose dependently compound 48/80-induced histamine release from rat peritoneal mast cells in a reversible manner. In contrast, budesonide did not appreciably affect the histamine release. Both orazipone and OR-1958 inhibit efficiently mast cell functions and therefore could prove useful in the treatment of diseases associated with inappropriate mast cell activation.
Vendelin
Johanna
J
Institute of Biomedicine, Department of Medical Chemistry, Finland.
Laitinen
Charlotta
C
Vainio
Petri J
PJ
Nissinen
Erkki
E
Mäki
Tiina
T
Eklund
Kari K
KK
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013439:Sulfhydryl Reagents / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C502618:OR 1958; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D013439:Sulfhydryl Reagents; D014409:Tumor Necrosis Factor-alpha; C502617:orazipone