Tumor necrosis factor-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis.

BACKGROUND: In vitro and animal studies suggest that tumor necrosis factor alpha (TNF-alpha) modulates intestinal iron transport. We hypothesized that the effect of TNF-alpha might be particularly relevant if iron absorption is not effectively controlled by the HFE gene. METHODS: In patients with homozygous C282Y hemochromatosis, we investigated the influence of TNF-alpha -308G>A allelic variant on total body iron overload, determined in all patients by measuring iron removed during depletion therapy, and hepatic iron index and need for phlebotomy to prevent iron reaccumulation, measured in patient subgroups. RESULTS: Of 86 patients with hereditary hemochromatosis, 16 (19%) were heterozygous carriers and 1 (1%) was a homozygous carrier of the TNF-alpha promoter -308A allele. Mean (SD) total body iron overload was increased 2-fold in TNF-alpha -308A allele carriers [10.9 (7.6) g] compared with homozygous carriers of the G allele [5.6 (5.0) g, P<0.001]. Hepatic iron index differed markedly between TNF-alpha -308A allele carriers [5.6 (3.5) micromol/g/year] and homozygous G allele carriers [3.1 (2.2) micromol/g/year, P=0.040, n=30]. After iron depletion, the need for phlebotomy to prevent iron reaccumulation (maintenance therapy) was substantially higher in TNF-alpha -308A allele carriers than in homozygous G allele carriers (P=0.014, n=73). We used multiple regression analyses to exclude possible confounding effects of sex, age, family screening, body-mass index, and meat or alcohol intake. CONCLUSION: TNF-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary (homozygous C282Y) hemochromatosis, but the effect of the TNF-alpha -308A allele on clinical manifestations of hemochromatosis was less accentuated than expected from the increased iron load associated with this allele.

Activation of pro-inflammatory and anti-inflammatory cytokines in host organs during chronic allograft rejection: role of endothelin receptor signaling.

This study investigated whether allograft rejection is associated with local inflammatory activation in host organs and whether endothelin ET(A) receptor signaling is involved. Expression of IL-1beta, IL-1ra, IL-6, IL-10 and TNF-alpha was investigated in host liver, lung and native heart in a rat model of chronic rejection 8 weeks after heterotopic cardiac transplantation in the absence of immunosuppression. In the presence of rejection, circulating levels of cytokines increased, while tissue level activation was dependent on the organ involved. Similarly, tissue-specific regulatory patterns were observed regarding transcriptional activation. Although chronic ET(A) receptor blockade did not reduce transplant vasculopathy or tissue protein expression, treatment had pronounced effects on plasma levels and transcriptional regulation of chemokines. These data provide evidence for distinct pro-inflammatory local activation in host organs during chronic rejection and suggest a role for ET(A) receptors contributing to regulation of cytokine plasma levels and transcriptional activity.

Roxithromycin treatment prevents progression of peripheral arterial occlusive disease in Chlamydia pneumoniae seropositive men: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Evidence has been provided that the atherosclerotic process may be associated with chronic infection with Chlamydia pneumoniae. The effect of antibiotic treatment on peripheral arterial occlusive disease has not been investigated yet. METHODS AND RESULTS: Forty C pneumoniae seropositive men suffering from peripheral arterial occlusive disease were randomly assigned to receive either roxithromycin (300 mg daily) or placebo for 28 days. During the 2.7-year follow-up, the number of invasive revascularizations per patient, the walking distance before intervention (in patients without intervention at study end), and the change of carotid plaque size were assessed. Five interventions were performed on 4 patients (20%) in the roxithromycin group, and 29 interventions were performed on 9 patients (45%) in the placebo group. Limitation of walking distance to 200 m or less was observed in 4 patients (20%) in the roxithromycin group and in 13 patients (65%) in the placebo group. The effect of macrolide treatment on the number of interventions per patient and on preinterventional walking distance was significant. Possible confounding variables such as classical vascular risk factors were excluded by multiple regression analyses. Carotid plaque areas monitored over 6 months decreased in the roxithromycin group (mean relative value, 94.4%) but remained constant in the placebo group (100.2%). Regression of carotid plaque size observed in roxithromycin-treated patients was significant for soft plaques. CONCLUSIONS: This study indicates that macrolide treatment for 1 month is effective in preventing C pneumoniae seropositive men from progression of lower limb atherosclerosis for several years.

Green tea polyphenols inhibit human vascular smooth muscle cell proliferation stimulated by native low-density lipoprotein.

This study investigated whether human vascular smooth muscle cell proliferation induced by native low-density lipoprotein (LDL) is affected by green tea catechins. Furthermore, the effects of native LDL on extracellular signal-regulated kinase (ERK) 1/2 activity were determined. Cell proliferation stimulated by native LDL was concentration-dependently inhibited by epigallocatechin, epigallocatechin-3-gallate, green tea polyphenon, and the nonspecific antioxidant N-acetylcysteine (P<0.05). Combined treatment of green tea polyphenon and N-acetylcysteine markedly potentiated the effect of each drug on vascular smooth muscle cell proliferation. ERK1/2 activity was only partly inhibited by green tea catechins alone or in combination with N-acetylcysteine (P<0.05). These data suggest that green tea constituents inhibit proliferation of human vascular smooth muscle cells exposed to high levels of native LDL. Green tea constituents and antioxidants may exert vascular protection by inhibiting human vascular smooth muscle cell growth associated with hypercholesterolemia.