Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Although evidence indicates that dehydroepiandrosterone (DHEA) exerts direct physiological effects, its mechanism of action remains unknown. DHEA binding sites were examined using a whole-cell binding assay in a human T lymphoid cell line, PEER, revealing that a single class of high-affinity binding sites for DHEA (dissociation constant = 7.4 +/- 0.53 nmol/L, mean +/- SE, n = 4) was greatly increased when treated with DHEA, phorbol-12-myristate-13-acetate, and the Ca2+ ionophore A23187. Bound [3H]DHEA was displaced sensitively by DHEA and secondarily by dihydrotestosterone, but not effectively by other steroids, including DHEA sulfate. These results not only indicate the existence of a DHEA receptor, but also suggest that T cells become susceptible to regulation by DHEA during the process of signal-induced activation.

Abstract. In human endometrium insulin-like growth factor binding protein (IGFBP)-1 inhibits the mitogenic action of insulin-like growth factor (IGF)-I by inhibiting the binding of IGF-I to its receptor. Our purpose was to compare circulating levels of IGF-I and IGFBP-1 in women with and without endometrial cancer. We assessed circulating levels of IGF-I and IGFBP-1 and IGFBP-3 in 23 patients with endometrial cancer, 11 patients with uterine cervical cancer and 27 healthy control women. The mean circulating level of IGF-I decreased significantly following menopause but was not correlated with age in the control group. The body mass index was significantly higher in the endometrial cancer group than in the control group. Analysis of covariance showed that even after the data were adjusted to eliminate the influence of the body mass index, the circulating IGF-I concentration was higher in postmenopausal endometrial cancer patients than in postmenopausal control subjects. The mean circulating level of IGFBP-1 was significantly lower in postmenopausal cancer patients than in postmenopausal control subjects. There were no significant differences in the serum levels of IGF-I and IGFBP-1 in the patients with cervical cancer and the control group. In conclusion, an increased circulating concentration of IGF-I and a decreased circulating concentration of IGFBP-1 are associated with endometrial cancer especially in postmenopausal women.

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