Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints
Spurlock III, Charles Floyd
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2014-03-21
Abstract
Rheumatoid arthritis is the most common serious autoimmune disease affecting almost one percent of the human population worldwide. Methotrexate is the most commonly used disease-modifying agent in patients with rheumatoid arthritis. Despite decades-long experience with the use of methotrexate in this disease, the mechanisms responsible for its activity in rheumatoid arthritis are not very well understood. Through a series of biochemical approaches and in vivo studies in patients with rheumatoid arthritis, we have defined two novel pathways contributing to the anti-inflammatory effects of methotrexate in T cells. The first pathway is dependent upon blockade of tetrahydropbiopterin biosynthesis resulting in increased activation of c-Jun-N-terminal kinase, restoration of cell cycle checkpoint deficiencies, and reduced levels of nuclear factor kappa B, a master regulator of inflammation. Finally, we also discovered that methotrexate induces expression of the long, intergenic non-coding RNA, lincRNA-p21. Independent of methotrexate-mediated blockade of tetrahydrobiopterin and increased activity of c-Jun-N-terminal kinase, induction of lincRNA-p21 by methotrexate also reduces indices of inflammation via blockade of nuclear factor kappa B activity. Thus, multiple pathways are responsible for the immunomodulatory effects of methotrexate in the treatment of rheumatoid arthritis.