Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice.

Abstract

Cytokines derived from macrophages (M) play a critical role in the development of type 1 diabetes in the nonobese diabetic (NOD) mouse. Based on earlier findings from lupus-prone strains of inherent cytokine defects in M , NOD M were evaluated for intrinsically dysregulated cytokine production with the potential to initiate or exacerbate disease. Endotoxin-activated peritoneal M from young prediseased NOD mice produced interleukin (IL)-1 and tumor necrosis factor (TNF)-␣ levels similar to those of M from a panel of control strains but reduced compared with the congenic diabetes-resistant NOR strain. IL-6 and IL-10 production were similar in NOD and NOR M, indicating that reduction in NOD IL-1 and TNF-␣ expression was selective. Nevertheless, the ratio of TNF-␣ and IL-10 production, a stringent index of normal M function, distinguished NOD from all normal strains. The most striking feature of NOD M, however, was their substantially elevated IL-12 production. This response was induced not only by endotoxin but also by bacillus Calmette-Guérin (BCG) and CD40 ligand and was associated with (and likely caused by) the enhanced and prolonged expression of p40 mRNA. Moreover, NOD M IL-12 expression appeared to be near maximally induced by lipopolysaccharide (LPS) alone, because it was only slightly enhanced by the addition of ␥-interferon, a stimulus that substantially elevated LPSinduced IL-12 production in M from normal strains. Accompanied by a unique profile of TNF-␣ and IL-10, the dramatic elevation of IL-12 expression by NOD M reflects intrinsic defects of the innate immune system with the potential to initiate and propagate the pathogenic autoreactive T-helper type 1 response characteristic of type 1 diabetes.

Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice

“…Previously, NOD mice were shown to have severe defects in their macrophage differentiation and function [31]. In this context, NOD macrophages are known to have a defect in IL1 expression upon stimulation with LPS [32]. Vitamin D-deficient mice generated in this study presented with an even bigger defect in IL1 and also IL6 secretion, probably due to a defect in macrophage differentiation in NOD mice lacking vitamin D in the diet.…”

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

“…23,24 The closely-related NOR strain 18 did not show such elevated expression. Since NOD and NOR mice differ in their Il12b coding sequences, it is likely that other linked but as yet unidentified polymorphisms in the promoter or other regulatory elements may differentially regulate IL-12p40 expression.…”

Aberrant Production of IL-12 by Macrophages from Several Autoimmune-Prone Mouse Strains Is Characterized by Intrinsic and Unique Patterns of NF-κB Expression and Binding to the IL-12 p40 Promoter

“…We had shown earlier that both NZB/W and MRL/ϩ M show a striking deficiency of IL-12 p40 and p70 production compared with M from the normal A/J strain (7), and that NOD M produce substantially higher levels than normal (9). These studies had compared the autoimmune-prone strains to an extensive panel of normal strains, verifying both the relatively consistent behavior of M from the normal strains and the polarized behavior of M from the lupus strains compared with NOD.…”

“…Macrophages (M ) 3 from several autoimmune-prone mouse strains are characterized by intrinsic defects in cytokine production (3)(4)(5)(6)(7)(8)(9). These defects can be elicited ex vivo before the onset of disease signs, and the intrinsic nature of some of the cytokine defects has been established (10).…”