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Originally published online as doi:10.1189/jlb.0703328 on February 24, 2004

Published online before print February 24, 2004
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(Journal of Leukocyte Biology. 2004;75:995-1000.)
© 2004 by Society for Leukocyte Biology

Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses

L. Vincent Collins*,1, Shahin Hajizadeh*, Elisabeth Holme{dagger}, Ing-Marie Jonsson* and Andrej Tarkowski*

* Department of Rheumatology and Inflammation Research, University of Göteborg, Sweden; and
{dagger} Department of Clinical Chemistry, Sahlgrenska University Hospital, Göteborg, Sweden

1Correspondence: Department of Rheumatology and Inflammation Research, University of Göteborg, Guldhedsgatan 10A, 41346 Göteborg, Sweden. E-mail: vincent.collins{at}rheuma.gu.se

We report that mitochondrial DNA (mtDNA) is inflammatogenic in vitro and in vivo as a result of the presence of unmethylated CpG sequences and its oxidative status. Purified human and murine mtDNAs induced arthritis when injected intra-articularly (i.a.) in mice. Importantly, oligodeoxynucleotide that contained a single oxidatively damaged base also induced arthritis when injected i.a. in mice. In contrast, neither human nor murine nuclear DNA induced inflammation. mtDNA-induced arthritis was neither B cell- nor T cell-dependent but was mediated by monocytes/macrophages. mtDNA-induced nuclear factor-{kappa}B stimulation resulted in the production of tumor necrosis factor {alpha}, a potent, arthritogenic factor. Finally, extracellular mtDNA was detected in the synovial fluids of rheumatoid arthritis patients but not of control subjects. We conclude that endogenous mtDNA displays inflammatogenic properties as a result of its content of unmethylated CpG motifs and oxidatively damaged adducts.

Key Words: inflammation • rheumatoid arthritis • monocytes/macrophages




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