Interleukin-6 production by activated human monocytic cells is enhanced byMK-571, a specific inhibitor of the multi-drug resistance protein-1

1 The intracellular transport of leukotriene Cc (LTC4) in hematopoietic cel ls such as human monocytes is controlled by an ATP dependent carrier encode d by the multidrug resistance protein1 (MRP1) gene whose function can be bl ocked by the compound MK-571. Since LTs play a major role in control of cyt okine expression in monocytes, we questioned whether blocking of the MRP1 m ediated function by MK-571 might affect cytokine production. 2 MK-571 strongly enhanced IL-6 expression at mRNA and protein level in lip opolysaccharide (LPS) and interleukin-l (IL-I) stimulated human monocytes g iving rise to 2.0+/-0.4 (x+/-s.d.) and 5.7+/-3.5 fold induction of IL-S pro tein secretion. The increase in IL-6 secretion was accompanied by an enhanc ed phosphorylation of p38 but not of c-Jun-N terminal kinase. 3 The involvement of the kinase signalling pathways was further analysed by using SB203580 and PD98059, specific inhibitors of the p38 and ERK1/2 sign alling route. MK-571 mediated upregulation of IL-6 in the presence of IL-I was partially attenuated by SB203580 and PD98059. Electrophoretic mobility shift assays demonstrated that MK-571 did not affect the IL-1 induced DNA b inding activity of Activator Protein-1 and Nuclear Factor-KB but rather enh anced the transactivational activity of an IL-6 promoter construct. Finally it was shown that the MK-571 mediated effects on IL-6 secretion could not be inhibited by the LT synthesis inhibitor SB203347 or by the anti-oxidant pyrrolidine dithiocarbamate (PDTC). 4 These results indicate that the membrane transporter MRP1 is involved in the regulation of IL-6 expression in activated human peripheral blood monoc ytes.