Abstract
Lipopolysaccharide (LPS)-activated monocytes and macrophages produce large quantities of pro-interleukin (IL)-1β but externalize little mature cytokine. Efficient post-translational processing of the procytokine occurs in vitro when these cells encounter a secretion stimulus such as ATP, cytolytic T cells, or hypotonic stress. Each of these stimuli promotes rapid conversion of 31-kDa pro-IL-1β to its mature 17-kDa species and release of the 17-kDa cytokine. In this study, two novel pharmacological agents, CP-424,174 and CP-412,245, are identified as potent inhibitors of stimulus-coupled IL-1β post-translational processing. These agents, both diarylsulfonylureas, block formation of mature IL-1β without increasing the amount of procytokine that is released extracellularly, and they inhibit independently of the secretion stimulus used. Conditioned medium derived from LPS-activated/ATP-treated human monocytes maintained in the absence and presence of CP-424,174 contained comparable quantities of IL-6, tumor necrosis factor-α (TNFα), and IL-1RA, but 30-fold less IL-1β was generated in the test agent's presence. As a result of this decrease, monocyte conditioned medium prepared in the presence of CP-424,174 demonstrated a greatly diminished capacity to promote an IL-1-dependent response (induction of serum amyloid A synthesis by Hep3B cells). Oral administration of CP-424,174 to mice resulted in inhibition of IL-1 in the absence of an effect on IL-6 and TNFα. These novel agents, therefore, act as selective cytokine release inhibitors and define a new therapeutic approach for controlling IL-1 production in inflammatory diseases.
Footnotes
- Abbreviations:
- IL
- interleukin
- LPS
- lipopolysaccharide
- CRID
- cytokine release inhibitory drug
- FBS
- fetal bovine serum
- ELISA
- enzyme-linked immunosorbent assay
- PMSF
- phenylmethylsulfonyl fluoride
- CTL
- cytotoxic T lymphocyte
- SFM
- serum-free medium
- PAGE
- polyacrylamide gel electrophoresis
- PBS
- phosphate-buffered saline
- TCA
- trichloroacetic acid
- LDH
- lactate dehydrogenase
- SAA
- serum amyloid A
- Received April 4, 2001.
- Accepted June 26, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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