Resistin-like Molecule Research Articles

Intestinal epithelial cell secretion of RELM-β protects against gastrointestinal worm infection

Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) β. RELM-β is essential for normal spontaneous expulsion and IL-4–induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC. RELM-β is nontoxic for H. polygyrus in vitro but directly inhibits the ability of worms to feed on host tissues during infection. This decreases H. polygyrus adenosine triphosphate content and fecundity. Importantly, RELM-β–driven immunity does not require T or B cells, alternative macrophage activation, or increased gut permeability. Thus, we demonstrate a novel mechanism for host protection at the mucosal interface that explains how stimulation of epithelial cells by IL-4 and IL-13 contributes to protection against parasitic helminthes that dwell in the intestinal lumen.

Expression of resistin-like molecule beta in gastric cancer: its relationship with clinicopathological parameters and prognosis

Resistin-like molecule beta (RELMbeta), an intestinal goblet cell-specific protein, is a biomarker of intestinal metaplasia in Barrett's esophagus and over-expressed in colon cancer. Since gastric adenocarcinomas can arise through a process of intestinalization, we hypothesized that RELMbeta might be aberrantly expressed in gastric cancer. This study was undertaken to examine the RELMbeta expression in gastric cancer and correlate it with clinical outcome. One hundred and thirty-six gastric cancer patients were evaluated for the RELMbeta expression by immunohistochemistry. The RELMbeta transcripts were measured by real-time quantitative PCR. In normal gastric mucosa, RELMbeta expression was absent, whereas areas of intestinal metaplasia revealed RELMbeta reactivity. Eighty-nine patients of gastric cancer (65.4%) were positive for RELMbeta expression. In a subtotal of 20 patients, RELMbeta transcripts were positively correlated with protein levels in gastric cancer tissues, but absent in normal gastric mucosa. The expression rate of RELMbeta was higher in intestinal-type carcinomas than in diffuse-type carcinomas (P < 0.001). RELMbeta positivity in gastric cancer was positively correlated with tumor differentiation (P = 0.001) and inversely correlated with tumor infiltration (P = 0.007), lymph node metastasis (P = 0.035), and heparanase expression (P < 0.001), without correlation with age, gender, tumor location and size, tumor-node metastasis stages, and Ki-67 expression. Patients showing positive RELMbeta expression had a significantly longer overall survival than those with negative expression (P = 0.001). These results provide evidences that the RELMbeta expression in gastric cancer is correlated with clinicopathological features and may be a useful prognostic factor for predicting the outcome of gastric cancer patients.

IL-31-IL-31R Interactions Limit the Magnitude of Th2 Cytokine-Dependent Immunity and Inflammation following Intestinal Helminth Infection

IL-31 is a recently identified cytokine made predominantly by CD4(+) Th2 cells and its receptor, IL-31R, is expressed by a number of cell types including monocytes, epithelial cells, and T cells. Originally identified as a potential mediator of inflammation in the skin, we recently reported a novel function for endogenous IL-31R interactions in limiting type 2 inflammation in the lung. However, whether IL-31-IL-31R interactions regulate immunity or inflammation at other mucosal sites, such as the gut, is unknown. In this study, we report a regulatory role for IL-31-IL-31R interactions in the intestine following infection with the gastrointestinal helminth Trichuris muris, immunity to which is critically dependent on CD4(+) Th2 cells that produce IL-4 and IL-13. IL-31Ralpha was constitutively expressed in the colon and exposure to Trichuris induced the expression of IL-31 in CD4(+) T cells. In response to Trichuris infection, IL-31Ralpha(-/-) mice exhibited increased Th2 cytokine responses in the mesenteric lymph nodes and elevated serum IgE and IgG1 levels compared with wild type mice. IL-31Ralpha(-/-) mice also displayed enhanced goblet cell hyperplasia and a marked increase in secretion of goblet cell-derived resistin-like molecule beta into the intestinal lumen. Consistent with their exacerbated type 2 inflammatory responses, IL-31Ralpha(-/-) mice exhibited accelerated expulsion of Trichuris with significantly decreased worm burdens compared with their wild type counterparts early following infection. Collectively, these data provide the first evidence of a function for IL-31-IL-31R interactions in limiting the magnitude of type 2 inflammatory responses within the intestine.

Retnla (Relmα/Fizz1) Suppresses Helminth-Induced Th2-Type Immunity

Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla−/− mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla−/− mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla−/− mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla−/− mice developed stronger Th2 responses, which could be reversed by exogenous rRelmα treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-γ, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

Alternatively activated macrophage-derived RELM-α is a negative regulator of type 2 inflammation in the lung

Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) α/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-α–deficient (Retnla−/−) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-α. After challenge with Schistosoma mansoni (Sm) eggs, Retnla−/− mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla−/− mice exhibited elevated expression of pathogen-specific CD4+ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM-α could bind to macrophages and effector CD4+ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla−/− AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-α in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4+ T cell responses.

Interleukin (IL)‐13 modulation of goblet cell function is dependent on state of differentiation

We have examined the effects of differentiation on responsiveness of human LS174T and HT‐29Cl.16E goblet cells (GC) to the inflammatory mediator IL‐13. Expression of the GC genes mucin 2 (MUC2), resistin‐like molecule beta (RETNLB), and trefoil factor 3 (TFF3) and the sulfotransferase (ST) genes carbohydrate (N‐acetylglucosamine 6‐O) sulfotransferase 5 (CHST5) and beta‐galactose‐3‐O‐sulfotransferase 2 (GAL3ST2) was measured at different stages of confluence and after stimulation with IL‐13 using RT‐qPCR. Sialo‐ and sulfomucin chemotypes were assessed by high iron diamine and alcian blue (HID/AB) staining. Expression of MUC2, TFF3, and RETNLB increased in HT‐29Cl.16E cells with days post‐confluence, consistent with GC differentiation, and with addition of IL‐13 to pre‐confluent cells. However, MUC2 and RETNLB expression decreased while TFF3 expression was unaltered in the more differentiated, post‐confluent HT‐29Cl.16E cells treated with IL‐13. CHST5 expression increased 20‐fold in pre‐confluent cells, but only 10‐fold in post‐confluent cells treated with IL‐13. Expression of CHST5 also increased in LS174T cells in response to IL‐13. HID/AB analysis corroborated an increase in sulfomucin production in response to IL‐13. Together the data demonstrate that IL‐13 modulation of GCs is dependent on state of differentiation and may stimulate mucin sulfation via effects on the CHST5 gene.

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-beta, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-beta is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblast-like cells. We also show that addition of recombinant RELM-beta induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-beta may be involved in the development of scleroderma-associated pulmonary hypertension.

Alternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable Microbial Killing

The prime function of classically activated macrophages (activated by Th1-type signals, such as IFN-gamma) is microbial destruction. Alternatively activated macrophages (activated by Th2 cytokines, such as IL-4 and IL-13) play important roles in allergy and responses to helminth infection. We utilize a murine model of filarial infection, in which adult nematodes are surgically implanted into the peritoneal cavity of mice, as an in vivo source of alternatively activated macrophages. At 3 wk postinfection, the peritoneal exudate cell population is dominated by macrophages, termed nematode-elicited macrophages (NeMphi), that display IL-4-dependent features such as the expression of arginase 1, RELM-alpha (resistin-like molecule alpha), and Ym1. Since increasing evidence suggests that macrophages show functional adaptivity, the response of NeMphi to proinflammatory Th1-activating signals was investigated to determine whether a switch between alternative and classical activation could occur in macrophages differentiated in an in vivo infection setting. Despite the long-term exposure to Th2 cytokines and antiinflammatory signals in vivo, we found that NeMphi were not terminally differentiated but could develop a more classically activated phenotype in response to LPS and IFN-gamma. This was reflected by a switch in the enzymatic pathway for arginine metabolism from arginase to inducible NO synthase and the reduced expression of RELM-alpha and Ym1. Furthermore, this enabled NeMphi to become antimicrobial, as LPS/IFN-gamma-treated NeMphi produced NO that mediated killing of Leishmania mexicana. However, the adaptation to antimicrobial function did not extend to key regulatory pathways, such as IL-12 production, which remained unaltered.

Expression of Resistin-like Molecule Beta in Barrett’s Esophagus: A Novel Biomarker for Metaplastic Epithelium

The formation of goblet cells characterizes the intestinal metaplasia of Barrett's esophagus (BE). Hematoxylin-eosin (HE) staining may fail to show intestinal metaplasia in BE, and PAS-Alcian Blue may present difficulties of interpretation due to its more heterogeneous staining. Recent evidence indicates that expression of resistin-like molecule beta (RELMbeta), a goblet cell-specific protein, is uniquely restricted to intestinal epithelium. However, it still remains largely unknown whether RELMbeta can be served as a biomarker for metaplastic epithelium of BE. In this study, 104 biopsy specimens of the distal esophagus from 88 suspected BE patients were collected, including 56 suspected intestinal metaplasia, 26 gastric type mucosa, and 22 squamous epithelium. We evaluated the RELMbeta expression in these biopsy specimens, and compared with those of CDX-2 immunostaining and PAS-Alcian Blue staining (pH 2.5). Of the suspected intestinal metaplasia specimens, 46 presented intestinal-type goblet cells and were immunostaining positive for RELMbeta and CDX-2, the remaining ten possessed only goblet cell mimickers and were not reactive with RELMbeta and CDX-2. Of the gastric-type mucosa specimens, none reacted with either RELMbeta or CDX-2. Moreover, the squamous epithelium was not reactive with RELMbeta and CDX-2. Acid mucin was present in goblet cells in all cases of BE and columnar cells in ten gastric specimens. In addition, the reactivity of RELMbeta was enhanced in six BE specimens with dysplasia. These results provide evidence that RELMbeta protein may be a novel biomarker to distinguish the intestinal-type goblet cells and goblet cell mimickers, and useful in the correct diagnosis of BE.

Resistin-Like Molecule α Decreases Glucose Tolerance during Intestinal Inflammation

Resistin-like molecule alpha (Relm-alpha) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-beta, and Relm-gamma. Resistin was initially defined based on its insulin resistance activity, but the family members are highly up-regulated in various inflammatory states, especially those involving intestinal inflammation. In this study, we report the role of Relm-alpha at baseline and following an experimental model of colitis. Relm-alpha was readily detected in the serum at baseline (4-5 ng/ml), and its level was regulated by energy uptake. Retnla(-/-) mice had decreased baseline circulating leptin levels, but displayed normal glucose, glucose clearance, and insulin levels. Following exposure to the oral innate trigger dextran sodium sulfate (DSS), a nonredundant proinflammatory role for Relm-alpha was uncovered as Retnla(-/-) mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-alpha regulated eosinophil-directed cytokines (e.g., IL-5, CCL11/eotaxin-1, and CCL5/RANTES) and IL-17 ex vivo. Consistently, DSS-treated Retnla(-/-) mice displayed substantially decreased eosinophil accumulation and decreased phosphorylation of NF-kappaB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-alpha was up-regulated, and DSS-treated Retnla(-/-) mice were markedly protected from hyperglycemia induced by glucose injection independent of changes in insulin levels. Retnla(-/-) mice were protected from increases in gut hormone serum levels of gastric inhibitory polypeptide and peptide YY that were induced following DSS treatment. These findings demonstrate a central proinflammatory role for Relm-alpha in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.

Mechanisms of Action of the Resistin-like Molecule (RELM)-β) in Asthmatic Airways Remodelling

RATIONALE: We have addressed the possible role of RELM-β in asthmatic airways remodelling. We hypothesized that 1) Expression of RELM-β is elevated in airways of asthmatics compared with controls; 2) The remodelling Th2-cytokine IL-13 increases RELM-β expression in airways epithelium in vitro and 3) RELM-β acts on fibroblasts to induce production of extracellular matrix protein. METHODS: ELISA was employed to measure concentrations of RELM-β in bronchoalveolar lavage fluid (BAL) and the serum obtained from asthmatics and controls (n = 10 for each group). The effects of IL-13 on the expression RELM-β in primary cultured airway epithelial cells was determined by ELISA and RT-PCR. Western blot and RT-PCR were used to evaluate the effects of RELM-β on the expression of extracellular matrix proteins and TGF-β2 in human lung fibroblast cells (MRC5) and primary cultured airway fibroblast cells. RESULTS: The mean concentration of RELM-β was elevated in BAL fluid but not serum of asthmatic patients compared to controls. IL-13 significantly enhanced RELM-β expression in primary cultured airway epithelial cells. RELM-β increased the expression of collagen I, but not collagen III in airway fibroblast cells at both the mRNA and protein levels (p < 0.01). Additionally, RELM-β increased TGF-β2 mRNA expression (p < 0.05). CONCLUSIONS: Our data suggest that IL-13 might contribute to increased expression of RELM-β in asthmatic airways which may in turn contribute to airways remodelling by induction of TGF-β2 and collagen I expression.

Oxidative Stress and Asthma: Proteome Analysis of Chitinase-like Proteins and FIZZ1 in Lung Tissue and Bronchoalveolar Lavage Fluid

Oxidative stress plays an important role in the development of airway inflammation and hyperreactivity in asthma. The identification of oxidative stress markers in bronchoalveolar lavage fluid (BALF) and lung tissue from ovalbumin (OVA) sensitized mice could provide new insight into disease pathogenesis and possible use of antioxidants to alleviate disease severity. We used two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the impact of the thiol antioxidant, N-acetylcysteine (NAC), on protein expression in a murine OVA model. At least six proteins or protein families were found to be significantly increased in BALF from OVA-challenged mice compared to a control group: Chitinase 3-like protein 3 (Yml), Chitinase 3-like protein 4 (Ym2), acidic mammalian Chitinase (AMCase), pulmonary surfactant-associated protein D (SP-D), resistin-like molecule alpha (RELMalpha) or "found in inflammatory 1" (FIZZ1), and haptoglobin alpha-subunit. A total of nine proteins were significantly increased in lung tissue from the murine asthma model, including Yml, Ym2, FIZZ1, and other lung remodeling-related proteins. Western blotting confirmed increased Yml/Ym2, SP-D, and FIZZ1 expression measured from BAL fluid and lung tissue from OVA-challenged mice. Intraperitoneal NAC administration prior to the final OVA challenge inhibited Yml/Ym2, SP-D, and FIZZ1 expression in BALF and lung tissue. The oxidative stress proteins, Ym1/Ym2, FIZZ1, and SP-D, could play an important role in the pathogenesis of asthma and may be useful oxidative stress markers.

Resistin-like molecule α enhances myeloid cell activation and promotes colitis

Resistin-like molecule (Relm) alpha is a secreted protein and a hallmark signature gene for alternatively activated macrophages. Relm-alpha is highly induced by allergic inflammatory triggers and perceived to promote tissue repair. Yet the function of Relm-alpha remains unknown. We sough to determine the role of Relm-alpha in dextran sodium sulfate (DSS)-induced colonic injury. The cellular source of Relm-alpha was determined after oral DSS-induced colitis. Retnla(-/-) mice were generated, subjected to DSS treatment, and monitored for disease progression (clinical and histopathologic features). Cytokine production in the supernatants of ex vivo colon cultures, and of LPS-stimulated macrophages incubated with Relm-alpha was assessed. Relm-alpha was administered intraperitoneally, and the cellular recruitment to the peritoneum was assessed. After innate intestinal stimulation with DSS, Relm-alpha was highly expressed by eosinophils and epithelial cells. Retnla gene-targeted mice were protected from DSS-induced colitis (eg, decreased diarrhea, rectal bleeding, colon shortening, disease score, and histopathologic changes). Relm-alpha coactivated IL-6 and TNF-alpha release and inhibited IL-10 release from LPS-activated bone marrow-derived macrophages. Consistent with these finding, colon cultures of DSS-treated Retnla(-/-) mice produced decreased IL-6 and increased IL-10 ex vivo. Furthermore, Retnla(-/-) mice had substantially decreased c-Jun N-terminal kinase phosphorylation in vivo. In vivo administration of Relm-alpha initiated cellular recruitment to the peritoneum, and Relm-alpha was able to induce eosinophil chemotaxis in vitro. These findings demonstrate a central proinflammatory role for Relm-alpha in colonic innate immune responses, identifying a novel pathway for regulation of macrophage activation.

Goblet Cell-Derived Resistin-Like Molecule β Augments CD4+ T Cell Production of IFN-γ and Infection-Induced Intestinal Inflammation

The secreted goblet cell-derived protein resistin-like molecule beta (RELMbeta) has been implicated in divergent functions, including a direct effector function against parasitic helminths and a pathogenic function in promoting inflammation in models of colitis and ileitis. However, whether RELMbeta influences CD4(+) T cell responses in the intestine is unknown. Using a natural model of intestinal inflammation induced by chronic infection with gastrointestinal helminth Trichuris muris, we identify dual functions for RELMbeta in augmenting CD4(+) Th1 cell responses and promoting infection-induced intestinal inflammation. Following exposure to low-dose Trichuris, wild-type C57BL/6 mice exhibit persistent infection associated with robust IFN-gamma production and intestinal inflammation. In contrast, infected RELMbeta(-/-) mice exhibited a significantly reduced expression of parasite-specific CD4(+) T cell-derived IFN-gamma and TNF-alpha and failed to develop Trichuris-induced intestinal inflammation. In in vitro T cell differentiation assays, recombinant RELMbeta activated macrophages to express MHC class II and secrete IL-12/23p40 and enhanced their ability to mediate Ag-specific IFN-gamma expression in CD4(+) T cells. Taken together, these data suggest that goblet cell-macrophage cross-talk, mediated in part by RELMbeta, can promote adaptive CD4(+) T cell responses and chronic inflammation following intestinal helminth infection.

Enhanced Expression of Resistin-like Molecule Beta in Human Colon Cancer and Its Clinical Significance

Previous studies have indicated that resistin-like molecule beta (RELM beta), an intestinal goblet cell-specific protein, is markedly increased in the intestinal tumors of min mice and over-expressed in a human colon cancer cell line. We hypothesized that RELM beta might be enhanced in human colon cancer. The aim of this study was to examine the clinical importance of RELM beta expression in colon cancer patients and to correlate its expression with various clinicopathological parameters, upstream regulatory molecule expression, tumor proliferative capacity, and patients' survival. Of the 80 colon cancer patients studied, 65 (81.25%) tested positive for RELM beta, mainly in the cytoplasm of colon mucosa. Contrasting sharply with the strongly RELM beta-positive tumors, normal colon mucous membrane was negative or weakly positive. RELM beta positivity in colon cancer was correlated with histological grade of differentiation and lymph node metastasis, but not with age, gender, tumor location and size, tumor infiltration, Dukes' stage, liver metastasis, and venous invasion. RELM beta expression was significantly correlated with the expression of transcription factor CDX-2 (P < 0.01) but not with that of proliferative index Ki-67 (P > 0.05). The mean postoperative survival time (2.76 years) of RELM beta-positive patients was significantly longer than that (1.26 years) of RELM beta-negative patients (P = 0.032). These findings support evidence of the enhanced RELM beta expression in colon cancer patients and suggest that further investigation is warranted to explore the role of RELM beta in colon cancer.

Resistin-like molecule β regulates intestinal mucous secretion and curtails TNBS-induced colitis in mice

Resistin and resistin-like molecule (RELM)beta comprise a novel class of cysteine-rich proteins secreted into the circulation implicated in hepatic insulin resistance and inflammation. RELMbeta is specifically produced by intestinal goblet cells but regulation of its expression and much of its local function are not elucidated. RELMbeta has been suggested to regulate colonic inflammation susceptibility, which is dependent on the mucosal barrier integrity. In this work we explored the physiopathological role of RELMbeta in the colon. Among agents tested, carbachol and gastrin were strong inhibitors of RELMbeta mRNA accumulation. We examined the effect of recombinant RELMbeta on mucin secretion by human mucus-secreting HT29-Cl.16E cells in culture and by mouse colonic goblet cells in vivo. RELMbeta upregulated MUC2 and M1/MUC5AC gene expression in HT29-Cl.16E cells. RELMbeta enhanced M1/MUC5AC secretion by human colonic HT29-Cl.16E cells and MUC2 secretion by murine intestinal goblet cells. RELMbeta exerted its action exclusively on the apical side of HT29-Cl.16E cells, in agreement with its luminal mucosecretagogue effect in mice. Its action required calcium, protein kinase C, tyrosine kinases, and extracellular-regulated protein kinase activities and was synergized by carbachol. An intracolonic RELMbeta challenge was performed in the trinitrobenzene sulfonic acid (TNBS)-murine model of colitis and macroscopic and histological scores were monitored. The macroscopic and histopathological severity of TNBS-induced colitis was significantly attenuated by RELMbeta pretreatment. A direct participation in maintaining the mucosal defense barrier can be ascribed to RELMbeta in line with a regulatory role in intestinal inflammation.

Comment on “Resistin-Like Molecule β (RELMβ/FIZZ2) Is Highly Expressed in the Ileum of SAMP1/YitFc Mice and Is Associated with Initiation of Ileitis”

Comment on “Resistin-Like Molecule β (RELMβ/FIZZ2) Is Highly Expressed in the Ileum of SAMP1/YitFc Mice and Is Associated with Initiation of Ileitis”

Response to Comment on “Resistin-Like Molecule β (RELM β/FIZZ2) Is Highly Expressed in the Ileum of SAMP1/YitFc Mice and Is Associated with Initiation of Ileitis”

We thank Wen et al. ([1][1]) for their comments regarding our recent article ([2][2]). Although SAMP1/YitFc mice have many features that closely resemble human Crohn’s disease including pathological and histologic features, cytokine profile activation, and beneficial response to treatments that

Resistin-like Molecule (RELM-β) Is Up-regulated In Asthmatic Airways: Potential Role In Airway Remodelling

Resistin-like Molecule (RELM-β) Is Up-regulated In Asthmatic Airways: Potential Role In Airway Remodelling

Pulmonary arterial remodeling induced by a Th2 immune response.

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH.