Date of Award

11-16-2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology & Immunology

First Advisor

David S. Bradley

Abstract

I demonstrated here that the presence of physiological amounts of boron was able to prevent the onset of and ameliorate ongoing collagen-induced arthritis (CIA). I also show a mechanism for boron's anti-inflammatory properties, in that boron was able to down regulate a number of pro-inflammatory mediators, all of which are under transcriptional control of NF-κB. Boron-supplemented diets, 2.0 mg B/kg and 12 mg B/kg, rendered CIA susceptible mice significantly more resistant to the onset of clinical arthritis, compared to mice fed boron-deficient chow, or commercial rodent chow. Dietary boron supplementation was also shown to prevent the onset of experimental autoimmune encephalomyelitis. The addition of dietary boron to the chow of mice manifesting clinical CIA, significantly ameliorated disease, while arthritic mice maintained on commercial rodent chow did not show improvement in their inflammatory symptoms. I then investigated the molecular influence of boron on inflammation, utilizing a murine macrophage line, J774-A1, stimulated with lipopolysaccharide (LPS) in the presence or absence of supplemental boron. LPS-stimulated J447-A1 cells grown in presence of 10 or 100 μmol boron had decreased expression of Tumor Necrosis Factor-α, Interlukin-1β, Macrophage Inflammatory Protein-1, and inducible Nitric Oxide synthase (TNF-α, IL-1β, MIP-1α, and iNOS) transcripts compared to LPS-stimulated J477-A1 cells in the absence of additional boron, as quantified by RT-PCR. The translation of TNF-α in LPS-stimulated J774-A1 cells was also down regulated when boron was present in the media. Each of these inflammatory factors is under the transcriptional control of NF-κB. The expression of p53, a regulatory transcription factor, was slightly increased in LPS-stimulated J447-A1 cells when boron was supplemented in the media. Finally the transcription level of Cu-Zn Superoxide Oxide Dismutase (Cu-Zn SOD) was not influenced by boron levels in LPS-stimulated J477-A1 cells. Taken together these data indicate that at least one of the targets of boron resulting in down regulation of inflammation is at a site upstream of cytokine gene activation in the NF-κB regulated pathway. These findings concur with other work suggesting that boron has an anti-inflammatory influence. They also indicate that physiological levels of dietary boron may provide an alternative therapy for inflammatory autoimmune diseases, such as human rheumatoid arthritis and multiple sclerosis.

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