Tumor necrosis factor-alpha: a continuum of liability between insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus and carcinoma (review).
In this review, tumor necrosis factor-alpha (TNF-alpha) is identified as the uniting principle linking the pathogenesis of insulin-dependent diabetes mellitus (IDDM), non-insulin dependent diabetes mellitus (NIDDM) and carcinoma. Elevated TNF-alpha initially increases, and then inhibits, the activity of a number of key enzymes involved in energy metabolism and major histocompatibility (MHC) class I molecule expression. These enzymes include: protein-tyrosine kinase (PTKase) and protein-tyrosine phosphatase (PTPase--enzymes involved in energy metabolism, cell proliferation and stimulation of the MHC class I molecule pathway. Of primary importance is the inhibiting effect of TNF-alpha on PTKase, since this induces insulin resistance in NIDDM and carcinoma, and PTPase, which inhibits MHC class I molecule expression. Studies have shown that IDDM is associated with an increase in PTPase activity which leads to overexpression of MHC class I molecules and a concomitant destruction of pancreatic beta cells. Conversely, carcinoma is associated with an inhibition of PTPase activity, which reduces the expression of MHC class I antigen expression on the cell surface thereby allowing malignant cells to escape immune surveillance. It will be argued that there is continuum of liability between these three conditions, initiated by the effect of TNF-alpha on these key enzymes.
Holden
R J
RJ
Medical Research Unit, University of Wollongong, NSW, Australia.
Pakula
I S
IS
Mooney
P A
PA
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000503:physiopathology*; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology / Q000503:physiopathology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015395:Histocompatibility Antigens Class I; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases