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Abnormal NF-B Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes¹

Zia U. A. Mollah^2,*, Saparna Pai^2,*, Craig Moore^*, Brendan J. O’Sullivan^*, Matthew J. Harrison^*, Judy Peng^*, Karen Phillips^*, Johannes B. Prins^*, John Cardinal and Ranjeny Thomas^3,*

^* Diamantina Institute for Cancer, Immunology, and Metabolic Medicine, University of Queensland and Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Queensland, Australia

Dendritic cell (DC) differentiation is abnormal in type 1 diabetes mellitus (T1DM). However, the nature of the relationship between this abnormality and disease pathogenesis is unknown. We studied the LPS response in monocytes and monocyte-derived DCs isolated from T1DM patients and from non-T1DM controls. In T1DM patients, late LPS-mediated nuclear DNA binding by RelA, p50, c-Rel, and RelB was impaired as compared with type 2 DM, rheumatoid arthritis, and healthy subjects, associated with impaired DC CD40 and MHC class I induction but normal cytokine production. In TIDM monocytes, RelA and RelB were constitutively activated, and the src homology 2 domain-containing protein tyrosine phosphatase (SHP-1), a negative regulator of NF-B, was overexpressed. Addition of sodium stibogluconate, a SHP-1 inhibitor, to DCs differentiating from monocyte precursors restored their capacity to respond to LPS in 60% of patients. The monocyte and DC NF-B response to LPS is thus a novel phenotypic and likely pathogenetic marker for human T1DM. SHP-1 is at least one NF-B regulatory mechanism which might be induced as a result of abnormal inflammatory signaling responses in T1DM monocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants 210237 and 351439 from the National Health and Medical Research Council, and by the Princess Alexandra Hospital Foundation. R.T. was supported by Arthritis Queensland and B.J.O. by a Queensland Government Smart State Fellowship.

² Z.U.A.M. and S.P. contributed equally to the work.

³ Address correspondence and reprint requests to Prof. Ranjeny Thomas, Diamantina Institute for Cancer, Immunology, and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia. E-mail address: r.thomas1{at}uq.edu.au

⁴ Abbreviations used in this paper: T1DM, type 1 diabetes mellitus; DC, dendritic cell; IKK, IB kinase; T2DM, type 2 diabetes mellitus; SHP-1, src homology 2 domain-containing protein tyrosine phosphatase; HC, healthy control; RA, rheumatoid arthritis; PB, peripheral blood; MFI, mean fluorescence intensity; TRAF6, TNFR-associated factor 6.

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