Induction of Functional IL-8 Receptors by IL-4 and IL-13 in Human Monocytes

Abstract

IL-8 and related Glu-Leu-Arg (ELR+) CXC chemokines are potent chemoattractants for neutrophils but not for monocytes. IL-13 and IL-4 strongly increased CXCR1 and CXCR2 chemokine receptor expression in human monocytes, macrophages, and dendritic cells. The effect was receptor- and cell type-selective, in that CCRs were not increased and no augmentation was seen in neutrophils. The effect was rapid, starting at 4 h, and concentration dependent (EC50 = 6.2 and 8.3 ng/ml for CXCR1 and CXCR2, respectively) and caused by new transcriptional activity. IL-13/IL-4-treated monocytes showed increased CXCR1 and CXCR2 membrane expression. IL-8 and related ELR+ chemokines were potent and effective chemotactic agents for IL-13/IL-4-treated monocytes, but not for untreated mononuclear phagocytes, with activity comparable to that of reference monocyte attractants, such as MCP-1. In the same cells, IL-8 also caused superoxide release. Macrophages and dendritic cells present in biopsies from Omenn’s syndrome and atopic dermatitis patients, two Th2 skewed pathologies, expressed IL-8 receptors by immunohistochemistry. These results show that IL-13 and IL-4 convert IL-8 and related ELR+ chemokines, prototypic neutrophil attractants, into monocyte chemotactic agonists, by up-regulating receptor expression. Therefore, IL-8 and related chemokines may contribute to the accumulation and positioning of mononuclear phagocytes in Th2-dominated responses.

Dendritic cells delivered inside human carcinomas are sequestered by interleukin‐8

“…A previous study has suggested that CXCR1 and CXCR2 were nonfunctional in DCs derived in culture with GM-CSF and IL-13 in spite of detectable expression of the receptors. 23 Reasons for the discrepancy between these data and our own might involve differentiation conditions of DCs in culture.…”

“…Several reports had demonstrated that IL-8 was secreted by malignant cells in human digestive carcinomas, 5,[35][36][37] while genetic evidence in mice indicated a role for IL-8 in angiogenesis and metastasis. We thought that the chemotactic activity of IL-8, previously characterized on polymorphonuclear leukocytes (PMNs), 6 monocytes 23 and endothelial cells, 8 could be involved in intratumoral retention of DCs, provided that DCs would respond to IL-8.…”

Macrophages Transfected with Adenovirus to Express IL-4 Reduce Inflammation in Experimental Glomerulonephritis

“…IL-4 has been shown to increase the expression of chemokine receptors CXCR1 and CXCR2, which are counter-receptors to IL-8 and Gro-␣, thus making monocyte/macrophages responsive to IL-8 (40). In addition we have recently demonstrated that blockade of Gro-␣ receptor on the macrophage surface reduces their ability to localize to inflamed glomeruli with NTN within 24 h of the onset of disease (4).…”

Up-Regulated Expression of the CXCR2 Ligand KC/GRO-α in Atherosclerotic Lesions Plays a Central Role in Macrophage Accumulation and Lesion Progression

“…In this regard, CXCR2 expression is highly regulated by cytokines such as IL-4, IL-10, and IL-13 and by other factors that may regulate vascular inflammation in vivo. [35][36][37][38] In the intermediate atherosclerosis stage, macrophages in the lesions of the CXCR2 Ϫ/Ϫ BMT mice were located more superficially on the lumenal side of the intima rather than dispersed throughout the intima as in the CXCR2 ϩ/ϩ BMT mice. Moreover, in the advanced stages of atherosclerosis, the lesions of the CXCR2 Ϫ/Ϫ BMT mice demonstrated little progression beyond the intermediate stage with a relatively marked decline in lesion macrophage staining.…”