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Title page for ETD etd-03212014-091439


Type of Document Dissertation
Author Spurlock III, Charles Floyd
URN etd-03212014-091439
Title Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Andrew J. Link, Ph.D. Committee Chair
Amy S. Major, Ph.D. Committee Member
Jonathan M. Irish, Ph.D. Committee Member
Subramaniam Sriram, M.B., B.S. Committee Member
Thomas M. Aune, Ph.D. Committee Member
Keywords
  • methotrexate
  • autoimmune disease
  • inflammation
  • rheumatoid arthritis
  • cell cycle checkpoints
  • c-Jun-N-terminal kinase
  • p53
  • tetrahydrobiopterin
  • long non-coding RNA
Date of Defense 2014-03-11
Availability unrestricted
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.
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