CCR6 is a receptor for CCL18 expressed on human lung fibroblasts from IPF lungs

Background: CCL18 is a chemokine released by alternatively activated macrophages binding to a yet unknown receptor. CCL18 induces collagen synthesis by fibroblasts thus indicating that the putative CCL18 receptor is expressed by human lung fibroblasts. Methods: To identify the receptor we screened a phage display library; the expression of the receptor was confirmed using conventional antibodies. FGF2 Release was measured by ELISA and expression of collagen and α-smooth muscle actin was estimated by quantitative PCR. Results: Phage-display experiments pointed to the CC-chemokine receptor 6 (CCR6) as CCL18-receptor. Staining lung tissue indicated CCR6 expression by AEC-II and fibroblasts in IPF lungs but not in tumour-free areas of resected lungs from SqC-patients. CCR6 was expressed by lung fibroblast lines derived from IPF lungs but was almost absent in lines from healthy areas of lung tissue from squamous carcinoma (SqC) patients. Spontaneous release of fibroblast growth factor 2 (FGF2) was very low in SqC-fibroblasts (71±25pg/ml) but significantly increased in IPF-fibroblasts (603±463pg/ml). Stimulation of fibroblasts with CCL18 induced a non-significant increase in FGF2 release in SqC-fibroblast lines (143±77pg/ml) but led to a significant increase in IPF lines (1194±601pg/ml) which was blocked by an anti-CCR6 antibody in IPF-fibroblast lines (783±632pg/ml) but not in SqC-lines (112±66pg/ml). Likewise, CCL18 induced an up-regulation of collagen I (coll-1) and αSMA expression. Again, induction of coll-I and αSMA expression was blocked by an anti-CCR6 antibody. Conclusion: Our data indicate that stimulatory effects of CCL18 on human lung fibroblasts are mediated via CCR6 (patent pending).