Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma

Selective expression of certain chemokine receptors by melanoma cells and the presence of their ligands in tissues might govern organ site-specific metastasis. Because the expression profile of chemokine receptors in tissues of melanocytic origin is unknown, we performed a comprehensive study on melanocytic tissue samples investigating the expression of 18 chemokine receptors at the mRNA level by real-time polymerase chain reaction, using a semiquantitative approach, and of 3 chemokine receptors (CXCR6, CCR9, and XCR1) at the protein level. We report on the de novo expression of CXCR6 in primary melanomas and melanoma metastases, but absence in melanoma cell lines and congenital nevi. CXCR4 and CCR1 were the only 2 chemokine receptors that were consistently expressed in melanocytes, melanoma cell lines, primary, and metastatic melanoma; CCR1 expression increased significantly over progression. CCR9 and XCR1 transcripts were found in melanocytic lesions, and expression was confirmed by immunohistochemistry. Transcripts for CCR10 were not found in any of the lesions, but in some melanoma cell lines. Expression of CCR7 was observed in primary melanomas and some metastases. CCR5 was exclusively expressed in primary melanomas and some cutaneous metastases. Results revealed a restricted and differential pattern of chemokine receptor expression in melanoma tissue, which varies substantially from the expression profile of melanoma cell lines and warrants functional studies on some receptors

8-Methoxypsoralen Plus Ultraviolet A Therapy Acts via Inhibition of the IL-23/Th17 Axis and Induction of Foxp3(+) Regulatory T Cells Involving CTLA4 Signaling in a Psoriasis-Like Skin Disorder

To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5. hTGF-beta 1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4(+)CD25(+) regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-beta 1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor ROR gamma t. PUVA induced the Th2 pathway and IL-10-producing CD4(+)CD25(+)Foxp3(+)Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti-IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA. The Journal of Immunology, 2010, 184: 7257-7267