Intelectin is required for IL-13-induced monocyte chemotactic protein-1 and -3 expression in lung epithelial cells and promotes allergic airway inflammation

Abstract

Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

“…Several genes or gene products in these pathways have been associated with abnormal lung development or lung disease (e.g., asthma, or COPD). Noteworthy transcripts in these categories/pathways included FGF receptor 3 (FGFR3) (41); hypoxia inducible factor 1, a subunit (HIF1A) (42); intelectin 1 (ITLN1) (43,44); and heme oxygenase 1 (HMOX1) (45,46).…”

Intelectin-1 Is a Prominent Protein Constituent of Pathologic Mucus Associated with Eosinophilic Airway Inflammation in Asthma

“…One possibility is that it participates in pathways of inflammation downstream of IL-13 (1). Indeed, studies in a mouse model of asthma suggest that ITLN-1 mediates IL-13-induced monocyte chemotactic protein-1 and -3 production in epithelial cells (8). Another possibility is that ITLN-1 is a component of airway mucus and contributes to pathologic mucus gel formation in disease.…”

Impact Of Adiponectin Overexpression On Allergic Airways Responses In Mice

“…For example, we observed a significant reduction in OVAinduced expression of Retnla, Itln1, Clca3, Agr2, and Alox15 mRNA in Adipo Tg versus WT mice (Figure 3). Intelectin [37] and Alox15 [42,46] have each been shown to contribute to allergic airways inflammation in mice. Thus, our data suggest that adiponectin-dependent reductions in BAL cells may have been secondary to changes in the expression of these genes.…”

“…Real-time PCR was used to measure changes in mRNA abundance of genes known to be strongly induced in the lungs by OVA challenge in this protocol [37][38][39][40][41][42][43][44]. In WT mice, inhalation of OVA significantly increased pulmonary expression of Retnla, Itln1, Alox15, Muc5ac, Cxcl9, Clca3, Agr2, and Il17a mRNA ( Figure 3 Figure 4(a)), although eosinophils were lower than those induced with the acute challenge protocol (Figure 2(a)).…”