IFN-γ/IL-6 and related cytokines in chronic spontaneous urticaria: evaluation of their pathogenetic role and changes during omalizumab therapy

BACKGROUND: Recent studies highlight that high levels of cytokines may precede the onset of many systemic autoimmune disorders and may also be related to chronic spontaneous urticaria (CSU) activity. METHODS: Eight patients with CSU candidate to omalizumab therapy were enrolled. Four healthy controls were included with the purpose of comparing baseline cytokine levels. We evaluated serum levels of IFN-γ, IL-2, 4, 6, 8, and 10, TNF-α, and GM-CSF. For the patient group, venous blood samples were drawn at T0, T1 (1 week after first drug administration), T2 (after 3 months), T3 (after 6 months), and in case of relapse. Cytokine levels were measured using the human cytokines 8-plex kit. Disease activity and effect of therapy were calculated by means of Urticaria Activity Score 7. RESULTS: Higher levels of IL-6 and IFN-γ were found in patients with CSU compared to those observed in the control group. Moreover, a common trend between these cytokines and the clinical history of disease could be hypothesized, with a decrease in levels of IFN-γ and IL-6 following remission of CSU with omalizumab treatment. Levels of other tested cytokines were similar between patients and healthy subjects. CONCLUSION: IFN-γ and IL-6 are proinflammatory cytokines that are strongly related to autoimmunity. Despite being limited by the small sample size, our data offer new insight into a better understanding of the pathogenesis of CSU and support the need for further investigations

Therapeutic Effect of Polymeric Nanomicelles Formulation of LY2157299-Galunisertib on CCl4-Induced Liver Fibrosis in Rats

Hepatic fibrosis (HF) is a major cause of liver-related disorders and together with cancer-associated fibroblasts can favor liver cancer development by modulating the tumor microenvironment. Advanced HF, characterized by an excess of extracellular matrix (ECM), is mediated by TGF- β1, that activates hepatic stellate cells (HSCs) and fibroblasts. A TGF-β1 receptor inhibitor, LY2157299 or Galunisertib (GLY), has shown promising results against chronic liver progression in animal models, and we show that it can be further improved by enhancing GLYs bioavailability through encapsulation in polymeric polygalacturonic-polyacrylic acid nanomicelles (GLY-NMs). GLY-NMs reduced HF in an in vivo rat model of liver fibrosis induced by intraperitoneal injection of CCl4 as shown by the morphological, biochemical, and molecular biology parameters of normal and fibrotic livers. Moreover, GLY-NM was able to induce recovery from HF better than free GLY. Indeed, the encapsulated drug reduces collagen deposition, hepatic stellate cells (HSCs) activation, prevents fatty degeneration and restores the correct lobular architecture of the liver as well as normalizes the serum parameters and expression of the genes involved in the onset of HF. In summary, GLY-NM improved the pharmacological activity of the free TGF- β1 inhibitor in the in vivo HF treatment and thus is a candidate as a novel therapeutic strategy

Association between vitamin D receptor polymorphisms, tight junction proteins and clinical features of adult patients with atopic dermatitis

Background: Few studies have explored the intricate connections between vitamin D receptor (VDR) gene polymorphisms, VDR, tight junction (TJ) protein expression and clinical features of atopic dermatitis (AD). Methods: From 43 adult AD patients, VDR polymorphisms were genotyped from peripheral blood samples using polymerase chain reaction-restriction fragment length polymorphism. VDR, occludin, claudin-1 and ZO-1 protein expression from skin lesion biopsies were assessed by immunohistochemistry. Results: The A1012G heterozygous VDR polymorphism exhibited a lower odds ratio (OR) for juvenile AD onset (OR: 0.046, 95% CI 0.004-0.51, p=0.012). In contrast, the presence of ≥2 homozygous VDR polymorphisms were significantly associated with positive skin prick test (SPT) (10/20, 50%) vs. negative SPT (1/23, 4.3%; p=0.0003). The most highly expressed TJ proteins in lesions of AD patients were claudin-1 and ZO-1, while VDR and occludin were less prevalent. A significant correlation was observed between ZO-1 expression and a body mass index ≥30 kg/m2 (OR: 12.1, 95% CI 1.06-137.9, p=0.045). Claudin-1 expression was associated with a positive SPT (OR: 8.23, 95% CI 1.04-65.5, p=0.046) and serum 25(OH)D levels were negatively correlated with ZO-1 expression (rho= -0.43, p=0.0058). Conclusion: This study provides novel insights into the relationship between VDR gene polymorphisms, VDR, TJ protein expression, and clinical features in adult AD patients, highlighting a significant role of vitamin D in the pathophysiology of this disease