The intelectins: a new link between the immune response to parasitic infections and allergic inflammation?

Abstract

GU AND COLLEAGUES PROPOSE that intelectin may be an important mediator of allergic airway inflammation and may represent a therapeutic target for this condition (2). These authors show that intelectin-2 protein expression was induced within 2 h following inhaled allergen exposure, localized to mucous cells in the airway epithelium, and was associated with the expression of the chemokines MCP-1 and MCP-3. The actions of MCP-1, also known as CCL2, include recruiting regulatory and effector leukocytes, stimulating histamine or leukotriene release from mast cells and basophils, inducing fibroblast production of transforming growth factor- and procollagen, and enhancing Th2 polarization (10). MCP-3, also known as CCL7, has been implicated in cellular activation and inflammatory mediator release by eosinophils and basophils (9). In in vitro experiments, these investigators found that treatment of murine MLE-12 alveolar epithelial cells with IL-13 induced expression of intelectin-1 and intelectin-2, as well as MCP-1 and MCP-3. IL-13 is a Th2 cytokine produced in allergic airway inflammation and has been deemed a central mediator of airway responsiveness and mucus expression (13). To test the hypothesis that intelectin-1 and intelectin-2 are responsible for the IL-13-mediated increase in MCP-1 and MCP-3, the authors created short hairpin RNA (shRNA) to inhibit intelectin-1 and intelectin-2 transcripts. Indeed, the shRNA specific for both intelectin-1 and intelectin-2 blocked IL-13-induced MCP-1 and MCP-2 expression. Given this in vitro link between intelectin-1 and -2 and these chemokines implicated in allergic airway inflammation, in vivo studies were performed, and mice whose airways were transfected with intelectin shRNA 1 day before inhalational allergen challenge had significantly inhibited MCP-1 and MCP-3 transcript levels, a 76% reduction in bronchoalveolar cell eosinophilia, and decreased inflammatory cell infiltration around the conducting airways. Unfortunately, the investigators neither studied the effect of intelectin antagonism on airway mucus expression nor on airway responsiveness, both of which seem obvious endpoints given IL-13’s regulation of these physiological parameters. The consideration that intelectins may be important mediators of allergic airway inflammation is relatively recent and has slipped under the radar of many who study asthma. Komiya and colleagues (3) first cloned intelectin in 1998 using a large-scale in situ hybridization screening method and named the protein thusly because the amino acid sequence was similar to the oocyte lectin gene of Xenopus laevis. These investigators found that intelectin mRNA was expressed in the paneth cells of the small intestine, and they hypothesized that its function likely involved defense against microorganisms. Tsuji and colleagues (11) reported that human intelectin is a secretory glycoprotein expressed in the heart, small intestine, colon, and thymus. They further found that it bound to galactofuranosyl residues and recognized the bacterial arabinogalactan of Norcardia, positing that intelectin has a role in recognition of bacteria-specific components in host defense. Galactofuranosyl residues are present in bacterial and fungal cell walls, as well as in protozoan parasites, but not in mammalian cells. Lee and colleagues (5) identified two human homologs of the Xenopus lectin, which they termed HL1 and HL2. While these investigators reported that HL1 transcripts were found in the heart, small intestine, colon, thymus, ovary, and testis, HL2 transcripts were only present in the small intestine. Their analysis did not identify that either of these two intelectins were present in human lungs. Pemberton and colleagues (7) reported that mouse intelectin-2 expression was markedly increased in the paneth and goblet cells of BALB/c mice that are resistant to