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Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study.

ABSTRACT: OBJECTIVE:Interleukin-1 receptor antagonist (IL-1Ra), a natural inhibitor of interleukin-1 beta, has been shown to improve beta-cell function and glycemic control in patients with type 2 diabetes. The aim of this study was to investigate whether baseline systemic levels of IL-1Ra are associated with incident type 2 diabetes during more than 10 years of follow-up. RESEARCH DESIGN AND METHODS:We measured serum IL-1Ra concentrations in a nested case-control study (181 case and 376 age-, sex-, and BMI-matched normoglycemic control subjects) within the Whitehall II cohort (U.K.). RESULTS:IL-1Ra concentrations were higher in case subjects (P = 0.0006) and associated with incident type 2 diabetes (odds ratio for a 1-SD increase of IL-1Ra 1.48 [95% CI 1.21-1.80]). This association remained significant after adjustment for multiple potential confounders but was attenuated by adjusting for 2-h glucose. CONCLUSIONS:Our findings indicate that individuals who will develop type 2 diabetes are characterized by a complex immune activation that also includes upregulation of the anti-inflammatory cytokine IL-1Ra.

SUBMITTER: Herder C

PROVIDER: S-EPMC2646020 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study.

Herder Christian C Brunner Eric J EJ Rathmann Wolfgang W Strassburger Klaus K Tabák Adam G AG Schloot Nanette C NC Witte Daniel R DR

Diabetes care 20081210 3

<h4>Objective</h4>Interleukin-1 receptor antagonist (IL-1Ra), a natural inhibitor of interleukin-1 beta, has been shown to improve beta-cell function and glycemic control in patients with type 2 diabetes. The aim of this study was to investigate whether baseline systemic levels of IL-1Ra are associated with incident type 2 diabetes during more than 10 years of follow-up.<h4>Research design and methods</h4>We measured serum IL-1Ra concentrations in a nested case-control study (181 case and 376 ag ...[more]

PMID: 19073760

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Project description:Eicosanoids modulate both innate and adaptive immune responses in Mycobacterium tuberculosis (Mtb) infection and have been suggested as possible Host Directed Therapy (HDT) targets, but more knowledge of eicosanoid dynamics in Mtb infection is required. We investigated the levels and ratios of eicosanoid mediators and their cellular sources, monocyte subsets and CD4 T cells in Tuberculosis (TB) patients with various clinical states of Mtb infection. Patients consenting to prospective enrolment in a TB quality registry and biorepository, 16 with pulmonary TB (before and at-end-of treatment), 14 with extrapulmonary TB and 17 latently infected (LTBI) were included. Plasma levels of Prostaglandin E2 (PGE2), Lipoxin A4 (LXA4), and Leukotriene B4 (LTB4) were measured by enzyme-linked immunosorbent assay. Monocyte subsets and CD4 T cells and their expression of Cyclooxygenase-2 (COX-2), Prostaglandin receptor EP2 (EP2), and 5-Lipoxygenase (5-LOX) were analyzed by flow cytometry with and without Purified Protein Derivate (PPD)-stimulation. Pulmonary TB patients had elevated levels of the anti-inflammatory mediator LXA4 at diagnosis compared to LTBI (p < 0.01), while levels of PGE2 and LTB4 showed no difference between clinical states of Mtb infection. LTB4 was the only mediator to be reduced upon treatment (p < 0.05), along with the ratio LTB4/LXA4 (p < 0.01). Pulmonary TB patients had higher levels of total monocytes at diagnosis compared to end-of-treatment and LTBI (both p < 0.05), and a relative increase in the classical monocyte subset. All monocyte subsets had low basal expression of COX-2 and 5-LOX, which were markedly increased upon PPD stimulation. By contrast, the expression of EP2 was reduced upon stimulation. CD4 T cells expressed low basal COX-2 activity that increased modestly upon stimulation, whereas their basal expression of 5-LOX was considerable. In conclusion, the level of eicosanoids in plasma seem to vary between clinical states of Mtb infection. Mediators in the eicosanoid system are present in monocytes and CD4 T cells. The expression of eicosanoids in monocytes are responsive to mycobacterial stimulation independent of Mtb disease state, but subsets are heterogeneous with regard to eicosanoid-mediator expression. Further exploration of eicosanoid mediators as targets for HDT in TB are warranted.

Dataset Information

Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study.

Publications

Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study.

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