ABSTRACT
Macrophage migration inhibitory factor (MIF) is involved in eosinophil biology and in type 2 inflammation, contributing to allergic and helminthic diseases. We hypothesized that MIF participates in the pathogenesis of eosinophilic esophagitis (EoE), an allergic condition characterized by esophageal eosinophilic inflammation. MIF is highly expressed in esophageal mucosa of patients with EoE, compared with gastro-esophageal reflux disease and control patients, where it co-localizes predominantly with eosinophils. In vitro, recombinant MIF promotes human eosinophil chemotaxis, while MIF antagonist and CXCR4 antagonist, AMD3100, revert this effect. In a model of EoE induced by ovalbumin, Mif-deficient mice have reduced inflammation and collagen deposition compared with wild-type (WT) mice. Importantly, treatment of WT mice with anti-MIF or with AMD3100 during the challenge phase prevents accumulation of eosinophils and tissue remodeling. Conversely, recombinant MIF promoted tissue eosinophil inflammation in allergic mice. Together, these results implicate MIF in the pathogenesis of esophageal inflammation and suggest that targeting MIF might represent a novel therapy for EoE.
Subject(s)
Eosinophilic Esophagitis/immunology , Eosinophils/immunology , Intramolecular Oxidoreductases/immunology , Macrophage Migration-Inhibitory Factors/immunology , Adolescent , Adult , Animals , Benzylamines , Cyclams , Eosinophilic Esophagitis/genetics , Eosinophilic Esophagitis/pathology , Eosinophilic Esophagitis/therapy , Eosinophils/pathology , Female , Heterocyclic Compounds/pharmacology , Humans , Intramolecular Oxidoreductases/genetics , Macrophage Migration-Inhibitory Factors/genetics , Male , Mice , Mice, Knockout , Middle Aged , Mucous Membrane/immunology , Mucous Membrane/pathology , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/genetics , Receptors, CXCR4/immunologyABSTRACT
Ovariectomy leads to progressive and significant increases in body weight gain and osteoporosis and is related to changes in serum and tissue cytokine profiles, such as observed in other models of overweight. We aimed to evaluate serum interleukin-1beta and interleukin-10 shortly after ovariectomy, before the establishment of overweight in rats. Female Wistar rats were submitted to ovariectomy, ovariectomy and estradiol replacement, or sham operation and compared with intact controls. Rats were killed 3, 6, 9, or 13 d after ovariectomy. Body mass and retroperitoneal fats were significant higher only 13 d after ovariectomy, and estradiol replacement to ovariectomized rats impaired both body mass and retroperitoneal fat gain. Shortly after ovariectomy (at 3 d) serum interleukin-1beta levels significantly increased in ovariectomized rats, treated or not with estradiol, while serum interleukin-10 levels increased only 9 d after ovariectomy. Our results suggest the existence of an important interplay between the immune system and ovarian function. This interplay occurs regardless of significant changes in adipose tissue compartment, as ovarian excision leads to short-term changes in the pattern of interleukin-1beta and interleukin-10 cytokine production that precede body weight gain and are not reverted by estradiol replacement.
Subject(s)
Estradiol/pharmacology , Estrogen Replacement Therapy , Interleukin-10/blood , Interleukin-1beta/blood , Ovariectomy , Animals , Body Weight/drug effects , Body Weight/physiology , Estrogen Replacement Therapy/veterinary , Female , Intra-Abdominal Fat/anatomy & histology , Intra-Abdominal Fat/drug effects , Organ Size/drug effects , Rats , Rats, Wistar , Time FactorsABSTRACT
OBJECTIVE: Deregulated apoptosis might be involved in some of the features of Fanconi anaemia (FA). The possibility that the pro-apoptotic Bax protein could be involved in an increased susceptibility to apoptosis in FA patients was investigated. MATERIALS AND METHODS: Intracellular Bax expression, Bcl-2 expression (an anti-apoptotic protein) and cell death were analysed in 26 FA peripheral blood lymphocyte samples. RESULTS: Most FA samples (69%) displayed increased levels of Bax and were more susceptible to both spontaneous apoptosis and mitogen activation-induced cell death. Two subgroups were identified: one presented elevated levels of Bax (n = 18), whereas the other (n = 8), had Bax levels lower than controls. Two subgroups based on Bcl-2 expression were also identified: one with normal and another with high Bcl-2 expression. No inverse correlation was found between Bcl-2 levels and Bax expression. A clear difference in susceptibility to induced cell death could be observed between control and FA samples. The best correlation was observed between high levels of Bax and mitogen-induced apoptosis of cells; these displayed characteristics of necrosis secondary to apoptosis, suggesting that the intrinsic apoptotic pathway was being activated. CONCLUSION: Despite increased susceptibility to cell death induction, there was no correlation between Bax levels, chromosome breakage, haematological parameters or androgen therapy. The importance of apoptosis and Bax expression in the clinical development of FA awaits clarification.
