title: Novel thalidomide analogues from diamines inhibit pro-inflammatory cytokine production and CD80 expression while enhancing IL-10.
abstract: 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.
authors: Department of Parasitology, Microbiology and Immunology, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil.
authors: Luciano
authors: L
authors: Mazzoccoli
authors: Silvia H
authors: SH
authors: Cadoso
authors: Giovanni W
authors: GW
authors: Amarante
authors: Marcus V N
authors: MV
authors: de Souza
authors: Robert
authors: R
authors: Domingues
authors: Marco A
authors: MA
authors: Machado
authors: Mauro V
authors: MV
authors: de Almeida
authors: Henrique C
authors: HC
authors: Teixeira
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D003959:Diamines / Q000737:chemistry; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D018122:B7-1 Antigen; D016207:Cytokines; D003959:Diamines; D016753:Interleukin-10; D013792:Thalidomide