Epithelial interleukin-4 receptor expression promotes colon tumor growth

Abstract

Inflammatory mediators are of considerable interest as potential therapeutic targets in various cancers. Here we investigate whether interleukin (IL)-4 receptor alpha (IL4Ralpha), a component of the receptor complex for the T helper 2 cytokines IL4 and IL13, plays a role in colonic tumorigenesis. IL4Ralpha protein expression was seen in tumor cells of 28/48 human colon adenocarcinomas on a tissue microarray. In human and murine colon tumor cell lines analyzed in vitro, all of which expressed IL4Ralpha, treatment with exogenous ligand resulted in dose-dependent increases in proliferation. IL4 decreased apoptosis only in HCT116 cells. An orthotopic allograft model was used to determine in vivo effects of tumor cell-specific IL4Ra ablation. MC38 murine tumor cells with the IL4Ra gene knocked down showed reduced proliferation but no difference in apoptosis compared with controls after implantation in ceca of syngeneic mice. Mice null for IL4Ra and wild-type controls were treated with azoxymethane and dextran sulfate sodium to induce tumor formation. Mice with global deletion of IL4Ra had significantly fewer and smaller tumors. Reduced tumorigenicity correlated with decreased proliferation and increased apoptosis. Systemic blockade of IL4Ralpha-IL4 interactions with a chimeric soluble receptor protein gave similar results in the cecal implant model. Thus, IL4Ralpha, a component of the IL4R and IL13R, contributes to tumor formation in a mouse model of colitis-associated cancer. Proliferation appears to be directly mediated via IL4Ralpha on the epithelial tumor cells. Survival may be an indirect response mediated via other host cells. Our results support therapeutic targeting of IL4Ralpha in colon cancer.

Targeting of IL-4 and IL-13 receptors for cancer therapy

“…When IL-4 binds to IL-4Ra, it recruits one of two chains (cC or IL-13Ra1), depending on the cell type, forming a heterodimer complex that initiates signal transduction [42,43]. The type I IL-4R is generally present on lymphoid T and NK cells, basophils, mast cells and most mouse B cells; whereas type II IL-4R is found on non-lymphoid tumor cells [6,43]. Type III IL-4R is present on TF-1, B cells and monocytes.…”

“…Both IL-4 and IL-13 are structurally similar pleiotropic cytokines that regulate immune responses and the immune microenvironment, not only under normal physiological conditions, but also in cancer [3][4][5]. These immunoregulatory effector cytokines are produced predominantly by Th2 cells; but macrophages, dendritic cells, mast cells, natural killer T-cells (NKT), natural killer (NK) cells, basophils, and eosinophils also produce them [6]. The IL-13 gene bears a close structural and functional relationship to the IL-4 gene and has a 30% identity in the amino acid sequence to the IL-4 protein [4,7].…”

Interleukin-13 and its receptors in colorectal cancer (Review)

“…The studies on IL-13 and IL-13-related receptors as therapeutic targets have been mainly focused on asthma and allergic diseases (27,28,29,31,32) with substantial achievements (Table I).…”

Alternative activation of tumor-associated macrophages by IL-4

“…118,119 In addition, IL-4 may promote tumor growth by directly acting on tumor cells. Increased levels of IL-4R have been reported in a variety of human malignancies, [120][121][122][123][124][125] and IL-4 signaling in tumor cells has been shown to protect cells from apoptosis through upregulation of anti-apoptosis proteins including cFLIP, PED, Bcl-x L and Bcl-2.…”