alpha-Interferon potentiates epidermal growth factor receptor-mediated effects on human epidermoid carcinoma KB cells.

The molecular mechanisms underlying the growth inhibition of human tumor cells induced by recombinant interferon-alpha (IFN alpha) are mostly unknown. It has been proposed that this effect could be related to down-regulation and/or impaired function of peptide growth factor receptors (PGF-Rs) in tumor cells exposed to IFN alpha. However, we have previously described that IFN alpha-induced growth inhibition of human epidermoid carcinoma cells is paralleled by up-regulation of epidermal growth factor receptor (EGF-R). Here we report that an increase in EGF-R synthesis is detectable after 3 hr of exposure to cytostatic concentration of IFN alpha in epidermoid KB tumor cells. In these experimental conditions IFN alpha does not depress and even potentiates EGF-R function. IFN alpha-treated KB cells retain sensitivity to the cytotoxic activity of the anti-EGF-R 225 monoclonal antibody (MAb), which acts through receptor blockade, and are sensitized to the growth-promoting effect of EGF. EGF-induced tyrosine (tyr) phosphorylation both of total cellular protein extracts and of the immunoprecipitated EGF-R is increased in IFN alpha-treated cells. We conclude that a cross-talk between IFN alpha and EGF occurs in KB cells since IFN alpha, at cytostatic concentration, potentiates the effects mediated by the EGF-R.

Alpha-interferon induces depletion of intracellular iron content and upregulation of functional transferrin receptors on human epidermoid cancer KB cells.

We have demonstrated that interferon-alpha (IFN alpha) upregulates the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma cells. Here we report that IFN alpha induces growth inhibition and upregulation of transferrin receptor (TRF-R) on epidermoid cancer KB cells. IFN alpha does not alter TRF-R affinity for its ligand and induces a two-fold increase of TRF binding sites. IFN alpha does not modify receptor internalization and cycling. Intracellular iron levels are known to regulate TRF-R expression: we have, therefore, evaluated whether changes in the iron content could be determined by IFN alpha. Iron levels are transiently increased after addition of fresh growth medium in untreated controls but not in KB cells exposed for 48 h to IFN alpha. Iron depletion is however completely reversed 24 h later when maximal TRF-R upregulation occurs in IFN alpha-treated cells. We suggest that IFN alpha-induced iron depletion elicits a homeostatic cellular response through upregulation of TRF-R.

Linkage and linkage disequilibrium in chromosome band 1p36 in American Chaldeans with inflammatory bowel disease.

The idiopathic inflammatory bowel diseases (IBDs), consisting of Crohn's disease and ulcerative colitis, are complex genetic disorders involving chronic inflammation of the intestines. Multiple genetic loci have been implicated through genome-wide searches, but refinement of localization sufficient to undertake positional cloning efforts has been problematic. This difficulty can be obviated through identification of ancestrally shared regions in genetic isolates, such as the Chaldean population, a Roman Catholic group from Iraq. We analyzed four multiply affected American Chaldean families with inflammatory bowel disease not known to be related. We observed evidence for linkage and linkage disequilibrium in precisely the same region of chromosome band 1p36 reported previously in an outbred population. Maximal evidence for linkage was observed near D1S1597 by multipoint analysis (MLOD = 3.01, P = 6.1 x 10(-5)). A shared haplotype (D1S507 to D1S1628) was observed over 27 cM between two families. There was homozygous sharing of a 5 cM portion of that haplotype in one family and over a <1 cM region in the second family. Homozygous sharing of this haplotype near D1S2697 and D1S3669 was observed in one individual in a third multiply affected family, with heterozygous sharing in a fourth family. Linkage in outbred families as well as in this genetic isolate indicates that a pathophysiologically crucial IBD susceptibility gene is located in 1p36. These findings provide a unique opportunity to refine the localization and identify a major susceptibility gene for a complex genetic disorder.