Effects of 5-lipoxygenase inhibitors on interleukin production by human synovial tissues in organ culture: comparison with interleukin-1-synthesis inhibitors

J Pharm Pharmacol. 1996 Jan;48(1):46-52. doi: 10.1111/j.2042-7158.1996.tb05875.x.

Abstract

Prostaglandins and leukotrienes differentially regulate the production of interleukin-1 (IL-1) in monocytes. It was, therefore, decided to investigate the effects of some 5-lipoxygenase inhibitors compared with standard IL-1 synthesis inhibitors on the production of IL-1 by human synovial tissue explants in organ culture. Human synovial (from hip/knee arthroplasty) or porcine tibio-tarsal joint synovial explants were incubated in organ culture in Dulbecco's Modified Eagle's Medium + 5% foetal calf serum in the presence of the test compounds or solvents (controls), or media alone for 1-5 days. Total bioactive IL-1 was assayed in the medium (following serial dilution or with polyethylene glycol 8000 added in some assays to remove inhibitors) using the D-10 T-cell bioassay. Some assays of interleukins 1 alpha, 1 beta, 6 or 8 were performed by ELISA. Of the 5-lipoxygenase inhibitors investigated, MK-886(3-(1-(4-chlorobenzyl)-3-tert-butyl-thio-5-isopropylindol-2- yl)-2,2 -dimethyl propanoic acid), L-656,224 ((7-chloro-2-[4-methoxypenyl]methyl)-3 -methyl-5-propyl-4-benzofuranol), PF-5901 and tepoxalin were the most potent inhibitors of IL-1 production. While the PF-5901 was effective at 5-30 microM and tepoxalin was effective at 1-10 microM, the others were the most potent having minimal inhibitory activity in the range of 0.01-0.1 microM. The presumed IL-1-synthesis inhibitors, tenidap and IX-207,887, were inactive at concentrations of 30-50 microM. Leukotriene B4 (1-100 ng/mL-1) added to MK-886 (5 microM)-treated cultures reversed the inhibitory effects of the latter on IL-1, confirming the role of 5-lipoxygenase products in the regulation of IL-1 production. Addition of polyethylene glycol 8000 to MI-886-treated cultures eliminated the inhibitory effects of this drug, suggesting that this drug exerts its effects by promoting production of IL-1 inhibitors. MK-886 also inhibited synovial production of two other pleiotrophic cytokines which it regulates, IL-6 and IL-8. The results suggest that some 5-lipoxygenase inhibitors may be usefully employed in regulating production of those interleukins involved in joint cartilage destruction.

MeSH terms

  • Animals
  • Benzofurans / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Hip Joint
  • Humans
  • Hydroxyurea / analogs & derivatives
  • Hydroxyurea / pharmacology
  • Indoles / pharmacology
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / biosynthesis*
  • Knee Joint
  • Lipoxygenase Inhibitors / pharmacology*
  • Naphthalenes / pharmacology
  • Organ Culture Techniques
  • Oxindoles
  • Pyrazoles / pharmacology
  • Quinolines / pharmacology
  • Structure-Activity Relationship
  • Swine
  • Synovial Membrane / drug effects*
  • Synovial Membrane / metabolism
  • Tarsus, Animal
  • Thiazoles / pharmacology
  • Thiophenes / pharmacology

Substances

  • Benzofurans
  • Indoles
  • Interleukin-1
  • Lipoxygenase Inhibitors
  • Naphthalenes
  • Oxindoles
  • Pyrazoles
  • Quinolines
  • Thiazoles
  • Thiophenes
  • MK-886
  • alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol
  • L 656224
  • IX 207-887
  • ICI 211965
  • tenidap
  • tepoxalin
  • zileuton
  • Hydroxyurea