Endogenous TNF production differs between high and low diabetes incidence non-obese diabetic (NOD) mice.
Tumour necrosis factor (TNF) has been implicated in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). To investigate a possible role for TNF in IDDM we compared endogenous TNF production in two lines of non-obese diabetic (NOD) mice, NOD/Lt and NOD/WEHI, that have a high and low incidence of diabetes, respectively. Preliminary experiments had shown that the lower syngeneic mixed lymphocyte reaction (SMLR) in NOD/Lt mice could be corrected by TNF-alpha. Plasma TNF-alpha was measured in 8 week-old female non-diabetic mice primed with 1000 units IV of murine interferon gamma (IFN-gamma) followed after 3 hours by 5 micrograms IV of lipopolysaccharide (LPS). Two hours later plasma was collected and TNF measured by ELISA. Plasma TNF in NOD/Lt mice was 9.2 +/- 2.4 ng/ml (mean +/- SEM, n = 16) compared to 2.5 +/- 0.5 ng/ml in NOD/WEHI mice (n = 15) and 7.6 +/- 1.0 ng/ml in BALB/c mice (n = 14). Time course studies demonstrated higher levels of both immunoreactive and bioactive TNF in NOD/Lt compared to NOD/WEHI mice up to 4 hours post-stimulation. A separate group of female NOD/Lt mice had IFN-gamma/LPS-stimulated plasma TNF-alpha measured at 10 weeks and were followed to age 30 weeks. The mean stimulated plasma TNF-alpha level was consistently higher in those mice that developed diabetes compared to those that remained non-diabetic, the difference being significant when mice were 21 weeks of age. These results suggest that endogenous TNF-alpha production may be a trait marker of IDDM susceptibility.
Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia.
N
N
Chosich
E
E
Rockett
L C
LC
Harrison
D000818:Animals; D001681:Biological Assay / Q000379:methods; D002461:Cell Line, Transformed; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology*
D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha