The flavonoid quercetin induces hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibits cell proliferation by depleting intracellular iron.

Quercetin, a flavonoid with anti-oxidant, metal chelating, kinase modulating and anti-proliferative properties, can induce hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia, but its mechanism of action has not been determined. In this study we characterized the induction of HIF-1alpha and the inhibition of cell proliferation caused by quercetin in HeLa and ASM (airway smooth muscle) cells and examined the effect of iron on these processes. Furthermore, we investigated the relevance of the intracellular levels of quercetin to HIF-1alpha expression and cell proliferation. Our data demonstrate that quercetin depletes intracellular calcein-chelatable iron and that supplying additional iron from extracellular or intracellular pools abrogates the induction of HIF-1alpha by quercetin. Moreover, addition of iron reverses the quercetin-induced inhibition of DNA synthesis, cell proliferation and cycle progression, but to different extents, depending on cell type. We propose that quercetin stabilises HIF-1alpha and inhibits cell proliferation predominantly by decreasing the concentration of intracellular iron through chelation.

Cytokine levels in the sera of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder. Cytokines contribute an important but yet undefined role to its pathogenesis. OBJECTIVES: The present study aims to compare serum levels of cytokines involved in Th-1 and Th-2 immunity, such as interleukins (IL) IL-2, IL-4, IL-8, IL-10, interferon-gamma (IFN-gamma) and IL-12 (p40) in patients with IPF and healthy volunteers. Twenty patients with IPF and 40 healthy controls (HC) participated. METHODS: Cytokines were assessed by enzyme-linked immunoabsorbent assay (ELISA). RESULTS: Median values of serum IL-2, IL-8, IL-10, IL-12 (p40) were higher in the IPF than the control group: IPF group: 1.05 U/ml, 12.55, 10.13, 44.17 pg/ml; control group: 0.05 U/ml, 6.91, 0.75, 4.51 pg/ml, respectively (P<0.05). IFN-gamma serum levels were lower in the IPF (0.19 pg/ml) than in the control group (0.49 pg/ml). IL-4 values did not differ in a statistically significant way among the groups: 8.40 pg/ml in the IPF group, and 7.46 pg/ml in the control group (P>0.05). IL-4 positively correlated to fast expiratory volume in 1s (FEV1%) and forced vital capacity (FVC%), while IL-8 negatively correlated to the respective values (P<0.005). CONCLUSIONS: IL-2, IL-8, IL-10 and IL-12 (p40) were found to be elevated in the sera of patients with IPF. IFN-gamma was found to be decreased in the sera of patients with IPF.

ICAM-1, ICAM-2 and ICAM-3 in the sera of patients with idiopathic pulmonary fibrosis.

In order to test the serum levels of ICAM-1, ICAM-2 and ICAM-3 in patients with idiopathic pulmonary fibrosis (IPF), twenty patients with IPF and eleven with secondary interstitial fibrosis (SIF), as well as forty healthy volunteers (HV) were studied. Serum intracellular adhesion molecules (ICAM) 1, 2 and 3 were assessed by ELISA. Functional respiratory tests, which included spirometry and lung diffusing capacity were simultaneously performed. Median values of serum ICAM-1 and ICAM-2 were higher in the patients' than in the healthy volunteers' (HV) group: IPF group: 946.60 ng/ml and 400.14 ng/ml; SIF group: 901.58 ng/ml and 378.27 ng/ml; HV group: 308.40 ng/ml and 217.55 ng/ml, respectively (p<0.05). ICAM-3 serum levels were equal between the three groups. ICAM-2 negatively correlated to DLCO values. (p<0.005). It can be concluded that ICAM 1 and 2 are elevated in the sera of patients with pulmonary fibrosis. ICAM-2 might be associated with a more impaired clinical status.