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Background Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL-4 and IL-13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL-4 or IL-13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL-13 signal. Methods We systematically identified periostin-dependent expression profile using DNA microarrays. We then investigated whether IL-24 downregulates filaggrin expression downstream of the IL-13 signals and whether IL-13-induced IL-24 expression and IL-24-induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL-24 and activation of STAT3 in mite-treated mice and in AD patients. Results We identified IL-24 as an IL-13-induced molecule in a periostin-dependent manner. Keratinocytes are the main IL-24-producing tissue-resident cells stimulated by IL-13 in a periostin-dependent manner via STAT6. IL-24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL-13/periostin pathway. Wild-type mite-treated mice showed significantly enhanced expression of IL-24 and activation of STAT3 in the epidermis, which disappeared in both STAT6-deficient and periostin-deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL-24 expression was enhanced in the epidermis of skin tissues taken from AD patients. Conclusions The IL-13/periostin pathway induces IL-24 production in keratinocytes, playing an important role in barrier dysfunction in AD.

BACKGROUND A predisposition to exacerbations is being recognized as a distinct phenotype with "previous exacerbations" representing the strongest clinical factor associated with future exacerbation. Thus, to identify additional novel biomarkers associated with asthma exacerbations, "past exacerbation status" must be included as a confounding factor. OBJECTIVE This study aimed to characterize the clinical and biomarker features associated with asthma exacerbations in severe asthma. METHODS We evaluated clinical parameters from 105 severe asthmatics yearly for 3 years, as well as their exacerbation status. We classified the subjects into 3 groups: (i) consistent non-exacerbators (CNE, subjects who did not experience any exacerbation over the 3-year period); (ii) consistent frequent exacerbators (CFE, subjects with frequent exacerbation, defined as those who had 2 or more exacerbations within 1 year, throughout the 3-year period); and (iii) intermittent exacerbators (IE). We conducted multivariate analysis for comparisons among the groups for multiple factors, including several Th2-related biomarkers, in addition to the "past exacerbation status." RESULTS Thirty-nine subjects were classified as CNE, 15 as CFE, and 51 as IE. Frequent exacerbations in the previous year predicted exacerbations for the following year (P

Periostin has been suggested as a novel, phenotype-specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear.To examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics.Serum periostin was examined by ELISA in 1100 subjects aged 17-76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil-derived neurotoxin (U-EDN), and serum eosinophil cationic protein (S-ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life.Although median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U-EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma.We confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype-specific biomarker in asthma.

Background and objective Serum periostin is increased in asthma and serves as a surrogate marker for IL-13 activity in the lung. Serum levels of periostin are the most robust biomarker predicting a favourable response to the anti-IL-13 drug, lebrikizumab. We investigated the mechanisms of IL-13 stimulation of periostin, the polarized secretion of periostin and whether periostin would have a direct effect on mucin secretion by airway cells. Methods Normal human bronchial epithelial (NHBE) cells were cultured at air–liquid interface (ALI) in the presence of IL-13, and we evaluated the effect of the specific inhibitors, leflunomide (Janus kinase (JAK)/signal transducer and activator of transcription factor 6 (STAT6) inhibitor) or PD98059 (MEK/extracellular regulated protein kinase (ERK) inhibitor), on periostin production. We examined MUC5AC secretion from NHBE cells exposed to recombinant human (rh) periostin or IL-13 in the presence and absence of OC-20, a periostin-neutralizing antibody. Results IL-13 induced periostin protein which was predominantly secreted towards the basal surface of the cells. Periostin production was much greater from goblet cells than ciliated cells (P

Unfortunately this article [1] was published with an error in the Funding section. The BM4SIT project is not acknowledged. This section should be corrected to the below: Funding EAACI and the BM4SIT project (Grant Number 601763) in the European Union’s Seventh Framework Programme FP7.

Proliferative vitreoretinopathy (PVR) is a severe, vision-threatening disorder characterized by the fibrous membrane formation that leads to tractional retinal detachment. There has been no effective therapeutic approach other than vitreoretinal surgery. In this study, DNA microarray analysis of the fibrous membranes revealed significant up-regulation of periostin. We also found increased periostin expression in the vitreous and retinal pigment epithelial (RPE) cells from fibrous membranes of PVR patients. In vitro, periostin increased proliferation, adhesion, migration, and collagen production in RPE cells through integrin αV-mediated FAK and AKT phosphorylation. Periostin blockade suppressed migration and adhesion induced by TGFβ2 and PVR vitreous. In vivo, periostin inhibition had the inhibitory effect on progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells. These results identified periostin as a pivotal molecule for fibrous membrane formation as well as a promising therapeutic target for PVR.

Cutaneous wound repair is a highly ordered and well-coordinated process involving various cell lineages and many molecular effectors. Cell-matrix interactions through integrin molecules provide key signals important for wound repair. Periostin is a matricellular protein that may provide signals important during tissue development and remodelling by interacting with several integrin molecules, via the phosphatidylinositol 3-kinase/Akt and MAP kinase pathways. In this study, we examined the role of periostin in the process of cutaneous wound repair using periostin-deficient mice and by analysing the effects of periostin on dermal fibroblasts. We first determined the expression profile and localization of periostin in a well-characterized wound repair model mice. Periostin was robustly deposited in the granulation tissues beneath the extended epidermal wound edges and at the dermal-epidermal junctions in wounded mice. Moreover, periostin-deficient mice exhibited delayed in vivo wound repair, which could be improved by direct administration of exogenous periostin. In vitro analyses revealed that loss of periostin impaired proliferation and migration of dermal fibroblasts, but exogenous supplementation or enforced periostin expression enhanced their proliferation. Combined, these results demonstrate that periostin accelerates the process of cutaneous wound repair by activating fibroblasts.

We report a 6-year-old girl with amegakaryocytic thrombocytopenia, the first case of this rare congenital disorder not to have an MPL gene mutation. Although no mutations were identified in MPL, Mpl protein was absent in the platelets and TPO induced phosphorylation of the Janus tyrosine kinase 2 (Jak2) was not detected. In addition to the defect of Mpl, the patient demonstrated markedly reduced expression of glycoprotein VI (GPVI) in contrast to normal expression of other platelet-specific proteins GPIb alpha, GPIb beta, and GPIIb. To explore the causes for the absence of Mpl, the entire coding region of Jak2 and AML1 were sequenced and no mutations were identified. To our knowledge, this is the first report that describes a case of amegakaryocytic thrombocytopenia that is not caused by a mutation in MPL and demonstrates the severe impairment of GPVI expression on platelets.

Inhaled steroids are the most potent anti-inflammatory therapy commonly used in bronchial asthma. There are, however, a small number of asthmatic patients who do not respond to inhaled steroid-treatment. The stimulation of metabolism and excretion of inhaled drugs at bronchial tissues might lead to a decrease in the effect of the drugs, although the molecular mechanism of this resistance is unclear. In this study, we found that beclomethasone dipropionate (BDP) stimulated the expression of mRNAs for uridine 5'-diphosphate glucuronosyl transferase 2B4 and 2B11, and transporters such as multidrug resistance P-glycoprotein, multidrug resistance-associated protein 1 and 2 in cultured bronchial epithelial cells. It is possible that the individual differences of expression of drug metabolizing enzymes and transporters and their enhancement with BDP are implicated in the individual differences of reactivity over steroid medical treatment.

Aims: Hodgkin's disease (HD) is characterized by the presence of Hodgkin and Reed–Sternberg (H–RS) cells against a hyperplastic background of reactive cells such as lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and stromal cells. There is ample evidence to suggest that proliferation and survival of HD-derived cells is due to cytokine signalling. Recently, high expression of interleukin (IL)-13 was described in HD-derived cell lines. Here we investigated the possible involvement of IL-13 in the pathophysiology, especially autocrine pathways of H–RS cells. Methods and results: The expression of IL-13 and IL-13 receptor (IL-13R) was determined by immunostaining and reverse transcriptase-polymerase chain reaction in 39 cases of HD, including 17 cases with nodular sclerosis (NS) type, 19 cases with mixed cellularity (MC), and three cases with lymphocyte predominance (LP) type. Expression of IL-13 was confined to H–RS cells and a few lymphocytes. IL-13R was expressed in H–RS cells, lymphocytes, histiocytes, fibroblasts, and endothelial cells. H–RS cells of MC and NS types frequently expressed both IL-13 and IL-13R. However, the number of IL-13-positive H–RS cells was statistically higher in NS-type than in MC-type, but the number of IL-13R was similar. IL-13R-positive fibroblasts were frequently encountered in NS-type. H–RS cells of LP type rarely expressed IL-13. Conclusions: Our results suggest that IL-13 might be involved in autocrine pathways of H–RS cells and fibrosis at least in NS-type. Our results also indicated that in addition to the morphological and phenotypic differences, the neoplastic cells of LP type might be functionally different from H–RS cells of MC- and NS-types.

It is well known that v-Src phosphorylates various substrates on tyrosine residue and associates with tyrosine-phosphorylated proteins as well as proline-rich ligands through its SH2 and SH3 domains, respectively, thereby inducing oncogenic transformation. A signal pathway from the cell surface to genes in the nucleus, the Jak/STAT (signal transducers and activators of transcription) pathway, has been shown to be involved in the signal transduction mechanism mediated by many cytokines and growth factors. Although a member of the STAT family, STAT3 has been reported to be constitutively activated in several v-Src-transformed cells, and it still remains unknown whether Jak molecules, which act upstream of STATs, are involved in the v-Src-induced activation mechanism of STAT3. In this study, we analyzed activations of both Jak and STAT molecules using v-Src-transformed HAG-1 cells derived from a human gallbladder adenocarcinoma. STAT3 was found to be constitutively activated in v-Src-transformed HAG-1 cells, but not in either non-transformed mock-transfected or activated c-H-ras-transfected HAG-1 cells, even though the other known STAT molecules are expressed. Furthermore, both Jak-2 and Tyk-2 were constitutively activated only in v-Src-transformed HAG-1 cells. Association of v-Src with either STAT3 or the Jak molecules was not observed. No change of this activation was detected by either interferon (IFN)-α2a or IFN-γ, which had shown inhibitory effects on the growth of v-Src-transformed HAG-1 cells. These results raise the possibility that Jak-2 and Tyk-2 are both activated by v-Src, thereby contributing to the constitutive activation of STAT3 in the v-Src-transformed cells. J. Cell. Physiol. 175:220–228, 1998. © 1998 Wiley-Liss, Inc.

Inflammation and allergy drug design , Inflammation and allergy drug design , کتابخانه مرکزی دانشگاه علوم پزشکی تهران