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.
Cytokines derived from macrophages (Mø) 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 Mø , NOD Mø were evaluated for intrinsically dysregulated cytokine production with the potential to initiate or exacerbate disease. Endotoxin-activated peritoneal Mø from young prediseased NOD mice produced interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha levels similar to those of Mø 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 Mø, indicating that reduction in NOD IL-1 and TNF-alpha expression was selective. Nevertheless, the ratio of TNF-alpha and IL-10 production, a stringent index of normal Mø function, distinguished NOD from all normal strains. The most striking feature of NOD Mø, however, was their substantially elevated IL-12 production. This response was induced not only by endotoxin but also by bacillus Calmette-Guerin (BCG) and CD40 ligand and was associated with (and likely caused by) the enhanced and prolonged expression of p40 mRNA. Moreover, NOD Mø IL-12 expression appeared to be near maximally induced by lipopolysaccharide (LPS) alone, because it was only slightly enhanced by the addition of gamma-interferon, a stimulus that substantially elevated LPS-induced IL-12 production in Mø from normal strains. Accompanied by a unique profile of TNF-alpha and IL-10, the dramatic elevation of IL-12 expression by NOD Mø 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.
Alleva
D G
DG
Evans Memorial Department of Clinical Research, Boston University Medical Center, Massachusetts, USA.
Pavlovich
R P
RP
Grant
C
C
Kaser
S B
SB
Beller
D I
DI
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D012016:Reference Values; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12