By. Kang et al., Chloromethyl ketones inhibit interleukin-12 production in mouse macrophages stimulated with lipopolysaccharide, IMMUNOL LET, 70(2), 1999, pp. 135-138
Interleukin-12 (IL-12) plays a pivotal role in the development of;T-helper
type 1 (Th1) immune response, which may be involved in the pathogenesis of
chronic inflammatory autoimmune disorders. In this study, we investigated t
he effects of N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and
N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK), serine protease inhibito
rs, on the production of IL-12 from macrophages stimulated with lipopolysac
charide (LPS). TPCK and TLCK potently inhibited this LPS-induced IL-12 prod
uction in a dose-dependent manner. The effect of TPCK and TLCK on the IL-12
p40 promoter activation was analyzed by transfecting monocytic RAW264.7 ce
lls with p40 promoter-reporter constructs. The repressive effect maps to a
region in the p40 promoter containing a binding site for NF kappa B (p40-ka
ppa B). A. linker scan mutant of the p40-kappa B site abrogates the inhibit
ory effect on the p40 promoter, confirming the functional relevance of the
NF kappa B site. Our results show that TPCK and TLCK inhibit NF kappa B-med
iated IL-12 production in macrophages. (C) 1999 Elsevier Science B.V. All r
ights reserved.