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

D. G. Alleva, R. P. Pavlovich, C. Grant, S. B. Kaser, D. I. Beller
2000 Diabetes  
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
more » ... 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.
doi:10.2337/diabetes.49.7.1106 pmid:10909966 fatcat:6cr63mqql5bsrgu64cx22rx2ce