Synthesis of a novel thiazolidinedione and evaluation of its modulatory effect on IFN- γ , IL-6, IL-17A, and IL-22 production in PBMCs from rheumatoid arthritis patients.
Rheumatoid arthritis (RA) is an autoimmune disease frequently characterized by chronic synovitis of multiple joints. The pathogenesis of RA is complex and involves many proinflammatory cytokines as Th17 related ones. PPAR γ is a nuclear receptor activator that represses proinflammatory gene expression. Thus, this work aimed to synthetize a new thiazolidinedione (TZD) analogue based on a well-known anti-inflammatory and PPAR γ agonist activity of this ring and evaluate its anti-inflammatory activity. After chemical structure confirmation, the compound named 5-(5-bromo-2-methoxy-benzylidene)-3-(2-nitro-benzyl)-thiazolidine-2,4-dione TM17 was submitted to cytokine releasing inhibition and PPAR γ genetic modulation assays. The new compound showed no toxicity on human and murine cells, decreasing IL-6 secretion by murine splenocytes and reducing IL-17A, IL-22, and IFN- γ expression in peripheral blood mononuclear cells from patients with RA. TM17 was more efficient in modulating the mRNA expression of PPAR γ than its well-used TZD agonist rosiglitazone. Surprisingly, TM17 was efficient on IL-17A and IFN- γ reduction, like the positive control methylprednisolone, and presented a better effect on IL-22 levels. In conclusion, PBMCs obtained from RA patients under TM17 treatment present a significant reduction in IL-17A, IL-22, and IFN- γ levels, but not IL-6 when compared with nontreated cells, as well as increase PPAR γ mRNA expression in absence of stimulus addressing it as a promising molecule in RA treatment.
Serviço de Reumatologia do Hospital das Clínicas (HC), Universidade Federal de Pernambuco (UFPE), Rua Tereza Amélia, s/n, Cidade Universitária, 50670-901 Recife, PE, Brazil ; Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT-SG), Universidade Federal de Pernanbuco, (UFPE), Rua Tereza Amélia, s/n, Cidade Universitária, 50670-901 Recife, PE, Brazil.
Laurindo Ferreira
LF
da Rocha Junior
Moacyr Jesus Barreto de Melo
MJ
Rêgo
Mariana Brayner
MB
Cavalcanti
Michelly Cristiny
MC
Pereira
Marina Galdino da Rocha
MG
Pitta
Priscilla Stela Santana
PS
de Oliveira
Sayonara Maria Calado
SM
Gonçalves
Angela Luzia Branco Pinto
AL
Duarte
Maria do Carmo Alves
Mdo C
de Lima
Ivan da Rocha
Ida R
Pitta
Maira Galdino da Rocha
MG
Pitta
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis*; D003710:Demography; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000097043:Interleukin-22
D016207:Cytokines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000097043:Interleukin-22; C089946:2,4-thiazolidinedione