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Abnormal NF-kappa B function characterizes human type 1 diabetes dendritic cells and monocytes
Mollah, Zia U.A., Pai, Saparna, Craig Moore, O'Sullivan, Brendan J., Harrison, Matthew J., Peng, Judy, Phillips, Karen, Prins, Johannes B., Cardinal, John and Thomas, Ranjeny (2008-03-01) Abnormal NF-kappa B function characterizes human type 1 diabetes dendritic cells and monocytes. Journal of Immunology, 180 5: 3166-3175.
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| Author(s) |
Mollah, Zia U.A.
Pai, Saparna
Craig Moore
O'Sullivan, Brendan J.
Harrison, Matthew J.
Peng, Judy
Phillips, Karen
Prins, Johannes B.
Cardinal, John
Thomas, Ranjeny
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| Title |
Abnormal NF-kappa B function characterizes human type 1 diabetes dendritic cells and monocytes
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| Journal name |
Journal of Immunology
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| Publication date |
2008-03-01
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| Year available |
2008
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| Volume number |
180
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| Issue number |
5
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| ISSN |
0022-1767
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| Start page |
3166
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| End page |
3175
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| Total pages |
10
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| Place of publication |
Bethesda, M.D, U.S.A.
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| Publisher |
The American Association of Immunologists
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| Collection year |
2009
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| Language |
eng
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| Subject |
C1
920104 Diabetes
110703 Autoimmunity
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| Abstract |
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-{kappa}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-{kappa}B response to LPS is thus a novel phenotypic and likely pathogenetic marker for human T1DM. SHP-1 is at least one NF-{kappa}B regulatory mechanism which might be induced as a result of abnormal inflammatory signaling responses in T1DM monocytes.
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