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Cytokine Imbalance as a Common Mechanism in Both Psoriasis and Rheumatoid Arthritis.

ABSTRACT: Psoriasis (PS) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases. Previous studies showed that these two diseases had a common pathogenesis, but the precise molecular mechanism remains unclear. In this study, RNA sequencing of peripheral blood mononuclear cells was employed to explore both the differentially expressed genes (DEGs) of 10 PS and 10 RA patients compared with those of 10 healthy volunteers and the shared DEGs between these two diseases. Bioinformatics network analysis was used to reveal the connections among the shared DEGs and the corresponding molecular mechanism. In total, 120 and 212 DEGs were identified in PS and RA, respectively, and 31 shared DEGs were identified. Bioinformatics analysis indicated that the cytokine imbalance relevant to key molecules (such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), colony-stimulating factor 3 (CSF3), interleukin- (IL-) 6, and interferon gene (IFNG)) and canonical signaling pathways (such as the complement system, antigen presentation, macropinocytosis signaling, nuclear factor-kappa B (NF-?B) signaling, and IL-17 signaling) was responsible for the common comprehensive mechanism of PS and RA. Our findings provide a better understanding of the pathogenesis of PS and RA, suggesting potential strategies for treating and preventing both diseases. This study may also provide a new paradigm for illuminating the common pathogenesis of different diseases.

SUBMITTER: Tan Y

PROVIDER: S-EPMC5296610 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Cytokine Imbalance as a Common Mechanism in Both Psoriasis and Rheumatoid Arthritis.

Tan Yong Y Qi Qiu Q Lu Cheng C Niu Xuyan X Bai Yanping Y Jiang Chunyan C Wang Yang Y Zhou Youwen Y Lu Aiping A Xiao Cheng C

Mediators of inflammation 20170125

Psoriasis (PS) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases. Previous studies showed that these two diseases had a common pathogenesis, but the precise molecular mechanism remains unclear. In this study, RNA sequencing of peripheral blood mononuclear cells was employed to explore both the differentially expressed genes (DEGs) of 10 PS and 10 RA patients compared with those of 10 healthy volunteers and the shared DEGs between these two diseases. Bioinformatics network a ...[more]

PMID: 28239238

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Project description:IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), and is being investigated for the treatment of psoriasis. Both conditions can present in women of child-bearing potential, but pregnancy was an exclusion and discontinuation criterion in tofacitinib randomized controlled trials (RCTs) because of the unknown effects of tofacitinib on mother and child. Tofacitinib is a small molecule that has the potential to cross the placenta.ObjectiveThe objective was to report outcomes of pregnancy cases identified through April 2014 from tofacitinib RA/psoriasis RCTs, RA post-approval non-interventional studies, and spontaneous adverse-event reporting.MethodsPregnancy outcomes were categorized as follows: healthy newborn, medical termination, fetal death, congenital malformation, spontaneous abortion, or pending/lost to follow-up.ResultsOut of 9815 patients, 1821 female patients of child-bearing age were enrolled in the RA/psoriasis RCTs; 47 women became pregnant, including 33 who received tofacitinib monotherapy, 13 who received combination therapy with methotrexate (RA patients only), and one patient whose therapy was still blinded. No fetal deaths were reported. One congenital pulmonary valve stenosis (monotherapy, n = 1), seven spontaneous abortions (monotherapy, n = 4; combination therapy, n = 3), and eight medical terminations (monotherapy, n = 4; combination therapy, n = 3; blinded therapy, n = 1) were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Forty-four cases of paternal exposure to tofacitinib were reported (monotherapy, n = 43; combination therapy, n = 1), including five spontaneous abortions (monotherapy, n = 4; combination therapy, n = 1), 23 healthy newborns, and 16 pending/lost to follow-up.ConclusionsThe pregnancy outcomes reported in this small number of RA/psoriasis patients appear similar to those observed in the general population and in patients treated with biologic therapies for inflammatory diseases. However, definitive conclusions cannot be drawn, and pregnancy outcomes in patients receiving tofacitinib will continue to be monitored.

Project description:Hypoxia stimulates synovial hypoperfusion in rheumatoid arthritis (RA). TXNDC5 stimulates cellular proliferation in hypoxic conditions. We previously detected increased TXNDC5 expression in synovial tissues and blood from RA patients and demonstrated that the gene encoding TXNDC5 increased RA risk. The present study investigated the pathogenic roles of TXNDC5 in RA. Transgenic mice that over-expressed TXNDC5 (TXNDC5-Tg) were generated using C57BL/6J mice and treated with bovine collagen II to induce arthritis (CIA). Synovial fibroblasts from RA patients (RASFs) were cultured and incubated with TXNDC5-siRNA or CoCl(2), a chemical that induces hypoxia. CIA was observed in 80% of the TXNDC5-Tg, but only 20% of the wild-type mice (WT) developed CIA. The clinical arthritis scores reached 5 in the TXNDC5-Tg, but this index only reached 2 in the control mice. CIA TXNDC5-Tg exhibited clear pannus proliferation and bone erosion in joint tissues. A significant increase in CD4 T cells was observed in the thymus and spleen of TXNDC5-Tg during CIA. Serum levels of anti-collagen II IgG, IgG1 and IgG2a antibodies were significantly elevated in the mice. Increased cell proliferation, cell migration and TXNDC5 expression were observed in RASFs following incubation with 1 µM CoCl(2). However, this effect was diminished when TXNDC5 expression was inhibited with 100 nM siRNA. TNF-alpha, IL-1α, IL-1β and IL-17 levels were significantly increased in the blood of TXNDC5-Tg mice, but the levels of these cytokines declined in the supernatant of RASFs that were treated with TXNDC5 siRNA. The expression of adiponectin, a cytokine-like mediator, decreased significantly in RASFs following TXNDC5 siRNA treatment. These results suggest that TXNDC5-over-expressing mice were susceptible to CIA. This study also suggests that hypoxia induced TXCNDC5 expression, which contributed to adiponectin expression, cytokine production and the cellular proliferation and migration of fibroblasts in RA.

Dataset Information

Cytokine Imbalance as a Common Mechanism in Both Psoriasis and Rheumatoid Arthritis.

Publications

Cytokine Imbalance as a Common Mechanism in Both Psoriasis and Rheumatoid Arthritis.

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