Characterization of the CC Chemokine Receptor 3 on Human Keratinocytes

Abstract

CC chemokine receptors are expressed on hematopoietic cells, and these may impart selective homing of monocyte, leukocyte, and lymphocyte subsets to sites of inflammation. CC chemokine receptor 3 is the major receptor on eosinophils and is also expressed on other inflammatory cells suggesting its important role for allergic diseases such as atopic dermatitis and bronchial asthma. Eotaxin, eotaxin-2 and eotaxin-3 have been identified as ligands that only activate CC chemokine receptor 3. CC chemokine receptor 3 is also activated by other promiscuous ligands, however, such as RANTES and monocyte chemotactic protein 4. To date, CC chemokine receptor 3 has not been reported to be expressed on nonhematopoietic cells. In this study, we investigated whether keratinocytes possess autocrine and paracrine mechanisms for CC chemokine secretion and receptor expression as reported for the expression of interleukin 8 and its receptors. Reverse transcriptase polymerase chain reaction analysis demonstrated that CC chemokine receptor 3 mRNA is expressed constitutively in cultured keratinocytes. The signal quantities of the CC chemokine receptor 3 amplicons showed lower intensities for keratinocytes than for eosinophils. In situ hybridization techniques exhibited that basal cell layers of the epidermis were stained homogeneously for CC chemokine receptor 3 mRNA with a decreasing signal to the upper epidermis showing that differentiating and proliferating keratinocytes did express mRNA specific for CC chemokine receptor 3. Immunohistochemical studies confirmed low expression of CC chemokine receptor 3 protein on epidermal keratinocytes compared to the high level observed on infiltrating eosinophils. Furthermore, stimulation of cultured keratinocytes with eotaxin resulted in an increased [3H]thymidine incorporation indicating a role of CC chemokine receptor 3 in epidermal proliferation and differentiation. These data demonstrate that CC chemokine receptor 3 is expressed not only on hematopoietic cells but also on keratinocytes as nonhematopoietic cells with ectodermal origin. Therefore, the identification of CC chemokine receptor 3 on epidermal keratinocytes may indicate a role for CC chemokine receptor 3 and its ligands in skin physiology and pathophysiology.

The CC chemokine eotaxin/CCL11 has a selective profibrogenic effect on human lung fibroblasts

“…We therefore limited subsequent in vitro experiments to the HLF line. A proliferative effect of eotaxin/CCL11 has been reported for keratinocytes, 42 and the intensity of the effect was comparable with that observed in our system. Pulmonary and activation-regulated chemokine (PARC)/CCL18, another CC chemokine with a profibrogenic effect, has been previously demonstrated to induce lung fibroblast proliferation 43 ; however, the effect of PARC/CCL18 was less pronounced than that of eotaxin/CCL11.…”

Autocrine Regulation of Re-Epithelialization After Wounding by Chemokine Receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3

“…However, their corresponding receptors (CCR4, CCR3, and CXCR4) were present on epidermal keratinocytes in vivo, and their ligands (CCL22, CCL24, and CXCL12) were able to induce migration and/or proliferation in vitro. In line with these results, chemokine CCL24 has been reported to be secreted by dermal fibroblasts and is known to induce keratinocyte proliferation Petering et al, 2001).…”

TGF-β differentially regulates TH2 cytokine-induced eotaxin and eotaxin-3 release by human airway smooth muscle cells

“…[34][35][36][37] In addition, CCR3 can be found on airway resident cells such as epithelial cells. 38,39 We have found expression of CCR3 on HASMs. 40 The finding of CCR3 on airway resident cells suggests that the ligands for CCR3 may not only function as chemokines for inflammatory cells.…”