1 Interleukin-12 (IL-12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-g and low IL-4 production. In this study we investigated whether retinoid-mediated inhibition of interleukin-12 production in mouse macrophages could regulate cytokine pro®le of antigen (Ag)-primed CD4 + Th cells. 2 Pretreatment with retinoids (9-cis-RA, all-trans-RA, TTNPB) signi®cantly inhibited IL-12 production by mouse macrophages stimulated with lipopolysaccharide (LPS) or heated-killed Listeria monocytogenes (HKL). Retinoid-pretreated macrophages reduced their ability to induce IFN-g and increased the ability to induce IL-4 in Ag-primed CD4 + T cells. 3 Addition of recombinant IL-12 to cultures of retinoid-pretreated macrophages and CD4 + T cells restored IFN-g production in CD4 + T cells. 4 The in vivo administration of 9-cis-RA resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine pro®le (decreased IFN-g and increased IL-4 production) in CD4 + T cells. 5 These ®ndings may explain some known e ects of retinoids including the inhibition of encephalitogenicity, and point to a possible therapeutic use of retinoids in the Th1-mediated immune diseases such as autoimmune diseases.

1 Transcription factors such as NF-kB provide powerful targets for drugs to use in the treatment of cancer. In this report parthenolide (PT), a sesquiterpene lactone of herbal remedies such as feverfew (Tanacetum parthenium) with NF-kB inhibitory activity, markedly increased the degree of human leukaemia HL-60 cell dierentiation when simultaneously combined with 5 nM 1a,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ). PT by itself did not induce HL-60 cell dierentiation. 2 Cyto¯uorometric analysis indicated that PT stimulated 1,25-(OH) 2 D 3 -induced dierentiation of HL-60 cells predominantly into monocytes. 3 Pretreatment of HL-60 cells with PT before the 1,25-(OH) 2 D 3 addition also potentiated the 1,25-(OH) 2 D 3 -induced HL-60 cell dierentiation in both a dose-and a time-dependent manner, in which the enhanced levels of cell dierentiation closely correlated with the inhibitory levels of NF-kB binding activity by PT. 4 In contrast, santonin, a sesquiterpene lactone without an inhibitory activity of NF-kB binding to the kB sites, did not enhance the 1,25-(OH) 2 D 3 -induced HL-60 cell dierentiation. 5 In transfection experiments, PT enhanced 1,25-(OH) 2 D 3 -induced VDRE-dependent promoter activity. Furthermore, PT restored 1,25-(OH) 2 D 3 -induced VDRE-dependent promoter activity inhibited by TNF-a, an activator of NF-kB signalling pathway. 6 These results indicate that PT strongly potentiates the 1,25-(OH) 2 D 3 -induced HL-60 cell dierentiation into monocytes via the inhibition of NF-kB activity and provide evidence that inhibition of NF-kB activation can be a pre-requisite to the ecient entry of promyelocytic leukaemia cells into a dierentiation pathway.

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