02725nas a2200409   4500000000100000008004100001260004700042653001200089653001700101653001400118653001400132653001300146653001900159653003100178653001100209653001700220653001900237653002800256653001600284653000900300653005200309653004100361653001600402100001700418700001300435700001500448700001500463700001600478700001400494700001500508700001500523245013400538300001000672490000700682520161200689022001402301       2012                            d  c2012 JulbMasson Pub. USA, Inc. aNew York10aAnimals10aB7-1 Antigen10aCell Line10aCytokines10aDiamines10aFlow Cytometry10aGene Expression Regulation10aHumans10aInflammation10aInterleukin-1010aLeukocytes, Mononuclear10aMacrophages10aMice10aReverse Transcriptase Polymerase Chain Reaction10aRNA Processing, Post-Transcriptional10aThalidomide1 aMazzoccoli L1 aCadoso S1 aAmarante G1 aSouza MV N1 aDomingues R1 aMachado M1 aAlmeida MV1 aTeixeira H00aNovel thalidomide analogues from diamines inhibit pro-inflammatory cytokine production and CD80 expression while enhancing IL-10.  a323-90 v663 a<p>Thalidomide is used to treat a variety of diseases including erythema nodosum leprosum, an inflammatory complication of leprosy. However, this drug has severe teratogenic activity and novel thalidomide analogues might be used to treat diseases without this severe side effect. A series of diamine compounds containing two hydrolyzed phthalimide units were chosen as analogues of thalidomide and evaluated regarding their capacity to regulate the production of molecules involved in inflammatory responses. TNF-α, IL-12 and IL-10 production, and the expression of CD80 and CD86 were investigated in LPS plus IFN-γ-stimulated J774A.1 cells by ELISA and flow cytometry, respectively. The expression of TNF-α and IL-10 mRNA was analyzed by real time RT-PCR. TNF-α, IL-6, IFN-γ, CXCL9 and CXCL10 production by human peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry. Compounds 3, 6 and 9 greatly inhibited TNF-α and IL-12 production while enhancing IL-10. In addition, CD80 expression was inhibited, but not CD86. The compounds inhibited TNF-α production by PBMC more than thalidomide and also had an inhibitory effect on the production of IL-6, IFN-γ, CXCL9 and CXCL10. Levels of mRNA for TNF-α were reduced after treatment with the compounds, suggesting post- transcriptional effects. The compounds had no effect on cell viability. Our results indicate that the novel diamine compounds 3, 6 and 9 inhibit critical pro-inflammatory cytokines and stimulate IL-10, which make them attractive candidate drugs for the treatment of certain inflammatory conditions and cancer.</p>  a1950-6007