Resistin-like molecule-β is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung

Abstract

Resistin-like molecule (RELM)-beta is a cysteine-rich cytokine implicated in insulin resistance and asthmatic responses, but its function remains an enigma. We now report that RELM-beta has a role in promoting airway inflammation and lung remodeling in the mouse lung. RELM-beta is strongly induced by diverse allergens and T helper type 2 (Th2) cytokines by an IL-13- and STAT6-dependent mechanism. To understand the in vivo role of RELM-beta, we delivered recombinant murine RELM-beta intratracheally to naïve mice. RELM-beta induced dose-dependent leukocyte accumulation (most prominently involving macrophages) and goblet cell hyperplasia. The most prominent effect induced by RELM-beta was increased perivascular and peribronchial collagen deposition. Mice genetically deficient in RELM-beta had reduced accumulation of collagen and goblet cell hyperplasia in an experimental model of allergic airway inflammation. In vitro experiments demonstrated that RELM-beta had fibroblast motogenic activity. These results identify RELM-beta as a Th2-associated cytokine with potent inflammatory and remodeling activity.

Resistin-like molecule- is a human airway remodelling mediator

“…Although RELM-b/FIZZ-2 expression has been reported in murine asthma ''models'' [4,7], there has been no systematic investigation of its expression in human airways diseases characterised by remodelling, most typically asthma, and its possible effects on human airway epithelial cells.…”

“…RELM-a/FIZZ-1 has never been observed in humans, in which species the gene does not appear to exist [6]. Conversely, RELM-b/FIZZ-2 is both expressed and highly conserved in mice and humans, especially in the C-terminus, which most resembles resistin [7]. It has been implicated in the mechanism of airway remodelling in a murine model of asthma [7] and is also clearly secreted into the lumen of the gut in mice [8], suggesting that it may function as a local mediator at a variety of epithelial surfaces.…”

“…Conversely, RELM-b/FIZZ-2 is both expressed and highly conserved in mice and humans, especially in the C-terminus, which most resembles resistin [7]. It has been implicated in the mechanism of airway remodelling in a murine model of asthma [7] and is also clearly secreted into the lumen of the gut in mice [8], suggesting that it may function as a local mediator at a variety of epithelial surfaces. In humans, it has been described as a product of epithelial, fibroblast and smooth muscle cells at sites of vascular remodelling [9].…”

Type 2 Innate Immunity in Helminth Infection Is Induced Redundantly and Acts Autonomously following CD11c+Cell Depletion

“…S1F in the supplemental material) in both isotype-and MAR-1 antibody-treated mice. An important innate effector in immune defense against H. polygyrus is RELM-␤, an IL-13-and STAT6-regulated product of mucosal epithelial cells (16,34). RELM-␤ expression was found to be highly elevated in intestinal tissue in both basophil-depleted and control mice (Fig.…”

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

“…Liu and colleagues (23) demonstrated that treatment of rat airway epithelial cells with recombinant IL-4 and IL-13 increases HIMF mRNA in a dosedependent manner, whereas the addition of Th1-related inflammatory cytokines (e.g., TNF-a) induces no such effect. Several reports have indicated that HIMF and its related molecules play a key role in the alternative (Th2) activation of macrophages (27,28), and are involved in Th2-dependent, asthma-induced airway remodeling (29). HIMF is also up-regulated in the newly described Th2 model of pulmonary arterial remodeling (30).…”