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Abnormal NF-κB Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes

2008; American Association of Immunologists; Volume: 180; Issue: 5 Linguagem: Inglês

10.4049/jimmunol.180.5.3166

1550-6606

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

Immune Cell Function and Interaction

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-κB, 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-κB response to LPS is thus a novel phenotypic and likely pathogenetic marker for human T1DM. SHP-1 is at least one NF-κB regulatory mechanism which might be induced as a result of abnormal inflammatory signaling responses in T1DM monocytes.