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Journal of Immunology Research
Volume 2016, Article ID 7509653, 12 pages
Research Article

Effect of N-Feruloylserotonin and Methotrexate on Severity of Experimental Arthritis and on Messenger RNA Expression of Key Proinflammatory Markers in Liver

1Department of Cell and Molecular Biology of Drugs, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia
2Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia
3Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague, Czech Republic
4Faculty of Food and Biochemical Technology, University of Chemistry and Technology, 166 28 Prague, Czech Republic
5Department of Galenic Pharmacy, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia

Received 22 February 2016; Revised 31 May 2016; Accepted 8 June 2016

Academic Editor: Oscar Bottasso

Copyright © 2016 Ľudmila Pašková et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Supplementary Material

Figure S1 Simplified overview of prominent pathways proposed to be involved in the transcription regulation of TNFα, iNOS and IL-1β in rheumatoid arthritis with the suggested effect of N-f-5HT. Binding of pro-inflammatory cytokines IL-1β and TNF-α to their respective competent receptors on target cells, IL1R1 and TNFR1, activate NF-κB and MAPKs pathways. MAPKs are regulated by several upstream phosphorylation cascades. Major MAPK families involved in the response to pro-inflammatory signals are the c-JUN N-terminal kinases (JNKs), ERK1/2 and the p38 enzymes. Similarly, binding of IL-6 or IFN-γ is activating the JAK-STAT pathway. Activated transcription factors: NF-κB for NF-κB pathway, AP-1 for MAPKs and STAT1 or STAT3 for JAK-STAT pathway translocate from the cytoplasm into the nucleus, where they bind to the promoters of responsive genes coding for various cytokines (including TNF-α and IL-1β) and other inflammatory molecules to activate the transcription. The mRNA expression of TNF-α is proposed to be mostly under control of NF-κB and AP-1, the expression of iNOS under control of NF-κB and STAT1, and the expression of IL-1β under control of NF-κB, AP-1 and STAT3. MTX is blocking the binding of IL-1β to IL1R. Both MTX and N-f-5HT have the potential to suppress NF-κB activation, MTX by well characterized mechanism of inhibition of IκB phosphorylation and subsequent release from the NF-κB complex. Both MTX and N-f-5HT inhibit the transcription of TNF-α and iNOS. In addition, N-f-5HT attenuates the transcription of IL-1β, presumably through STAT inhibition. IL, interleukin; TNF-α, tumor-necrosis factor α; IL1R, IL-1β receptor; TNFR1, TNF-α receptor; NF-κB, nuclear factor-κB; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinases; IFN-γ, interferon gamma; AP-1, activator protein-1; JAK, Janus kinase; STAT, signal transducers and activators of transcription; mRNA, messenger RNA; iNOS, inducible NO synthase; P, phosphorylation; N-f-5HT, N-feruloylserotonin; MTX, methotrexate; IκB, inhibitor of NF-κB.

  1. Supplementary Material