Rheumatoid arthritis inflammatory cells apoptosis

Methotrexate s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, inhibition of proinflammatory cytokines linked to rheumatoid synovitis has been shown, leading to decreased inflammation seen with rheumatoid arthritis. 

NF-kB comprises a family of inducible transcription factors that serve as relevant mediators of the inflammatory response. This factor is also involved in protecting cells from undergoing apoptosis in response to DNA damage or treatment with cytokine [89]. Normally, NF-kB is kept inactive by a cytoplasmic inhibitor of kB (IkB) proteins, which are phosphorylated by a cellular kinase complex known as IKK, made up of two kinases, IKK-a and IKK-p. The phosphorylation of IkB by these kinases leads to the degradation of the proteins and to the translocation of NF-kB to the nucleus. Once in the nucleus, NF-kB activates gene expression of cells exposed to growth factors and cytokines [90,91]. Activation of the NF-kB pathway is thus involved in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis and asthma... 

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