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

Abstract

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. PPARγ 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 PPARγ 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 PPARγ 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 PPARγ 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 PPARγ mRNA expression in absence of stimulus addressing it as a promising molecule in RA treatment.

Synthesis and bioevaluation of new 5-benzylidenethiazolidine-2,4-diones bearing benzenesulfonamide moiety

“…For E-configuration, the chemical shifts of these olefinic protons should be around 6.52 ppm. The exclusive formation of Z-isomer in this condensation reaction has also been clearly demonstrated by X-ray analysis (Bruno et al, 2002) and reported in many other similar studies (Alegaon and Alagawadi, 2012;da Rocha Junior et al, 2013).…”

Data integration for identification of important transcription factors of STAT6-mediated cell fate decisions

“…Furthermore, SATB1 coordinates Th2 cell differentiation by positively regulating Gata3 (Notani et al, 2010). SATB1, NFIL3, MAF, and PPARG positively regulate the gene expression of the Th2 cytokine Il4 (Ribeiro de Almeida et al, 2009;Kashiwada et al, 2011;Lai et al, 2012;da Rocha Junior et al, 2013;Kwon et al, 2014). In addition to the positive effects on Th2 cell differentiation, NFIL3 suppresses Th17 cell development by directly binding and repressing the Rorg promoter .…”

“…In addition to the positive effects on Th2 cell differentiation, NFIL3 suppresses Th17 cell development by directly binding and repressing the Rorg promoter . PPARG is also known to suppress Th17 and Th1 cell differentiation by decreasing the level of IFNγ production in splenocytes (da Rocha Junior et al, 2013 (Wuelling et al, 2009) Fifteen TFs were associated with the differentiation of other Th cell subtypes without a reported main function in Th2 cell differentiation. Of these, eight (Ah,Stat3,Etv6,Hif1α,Irf7,Stat2,Batf,and Crem) were increased, and seven (Irf1, Irf8, Nfatc3, Pou2af1, Rora, Klf2, and Tcf7) were decreased by STAT6.…”

Cytokine measurements in Brazilian postmenopausal osteoporosis patients reveal high levels of IL-8

“…Some factors encourage the uncoupling of osteoblastic and osteoclastic activities, such as RANK/RANKL/OPG, but little is known about inflammatory factors involved in this process. In inflammatory rheumatic diseases, the situation is worsened by the production of inflammatory cytokines such as TNF-α, IL-17A, IL-6 and, more recently, IL-22 [11]. The present study aimed to investigate serum levels of cytokines and to correlate them with clinical and laboratory parameters of postmenopausal osteoporosis.…”