The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPKsignaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.cancer ͉ CCL27/CTACK ͉ skin ͉ immune surveillance ͉ EGDR/R pathway

The proteolipid plasmolipin is member of the expanding group of tetraspan (4TM) myelin proteins. Initially, plasmolipin was isolated from kidney plasma membranes, but subsequent northern blot analysis revealed highest expression in the nervous system. To gain more insight into the functional roles of plasmolipin, we have generated a plasmolipin-specific polyclonal antibody. Immunohistochemical staining confirms our previous observation of glial plasmolipin expression and proves plasmolipin localization in the compact myelin of rat peripheral nerve and myelinated tracts of the CNS. Western blot analysis indicates a strong temporal correlation of plasmolipin expression and (re-) myelination in the PNS and CNS. However, following axotomy plasmolipin expression is also recovered in non-regenerating distal nerve stumps. In addition, we detected plasmolipin expression in distinct neuronal subpopulations of the CNS. The observed asymmetric distribution of plasmolipin in compact myelin, as well as in epithelial cells of kidney and stomach, indicates a polarized cellular localization. Therefore, we purified myelin from the CNS and PNS and demonstrated an enrichement of phosphorylated plasmolipin protein in detergent-insoluble lipid raft fractions, suggesting selective targeting of plasmolipin to the myelin membranes. The present data indicate that the proteolipid plasmolipin is a structural component of apical membranes of polarized cells and provides the basis for further functional analysis.

Plasmolipin is a membrane protein and belongs to the tetraspan molecule (4TM) family, an expanding group of myelin proteins many of which could be linked to human hereditary demyelinating neuropathies. We have cloned and sequenced the mouse plasmolipin gene, revealing the common organization of the 4TM gene group with four exons and a large first intron. Western blot analysis with an antibody raised against the C-terminal intracellular part of the protein showed that plasmolipin is expressed not only in the nervous system and kidney, but also in a number of other tissues such as thymus, testis, lung, and thyroid gland. By means of radiation hybrid mapping and FISH analysis, we could localize the human plasmolipin gene to Chromosome 16q13 within the putative region of the Bardet-Biedl syndrome type 2 (BBS2) gene locus. BBS2 is a clinically and genetically heterogeneous group of disorders resulting in rod-cone dystrophy, obesity, postaxial polydactyly, renal dysfunction, and mental retardation, which were very recently associated with a novel gene designated BBS2. With respect to intrafamiliar variations in the manifestation of BBS, we suggest that plasmolipin might be either another candidate gene or a modifier of the BBS2 phenotype.

Disintegrins perform putative functions in cell adhesion, signaling and fusion. We have isolated a 2815‐bp rat cDNA (CRII‐7) representing a transcript that is differentially expressed during sciatic nerve regeneration. Nucleotide sequence comparison indicates that CRII‐7 is the rat homologue to the recently cloned cDNAs MDC15 (ADAM 15) and metargidin (hMDC15) of mouse and human, respectively. The CRII‐7 cDNA (rMDC15) encodes a membrane‐anchored glycoprotein of approximately 85 kDa containing a disintegrin and a metalloprotease domain. Cellular metalloprotease disintegrins are a family of proteins (ADAMs or MDC proteins) with important roles, e.g., in cell–cell interactions during fertilization, muscle and nerve development, or tumor necrosis factor‐α (TNF‐α) cleavage. Northern blot analysis demonstrated a predominant expression of CRII‐7/rMDC15 in the nervous system (PNS and CNS) and lung. Analysis of the CRII‐7/rMDC15 transcript levels following peripheral nerve lesions demonstrated regulated mRNA expression during Wallerian degeneration and nerve regeneration. The steady‐state levels of CRII‐7/rMDC15 transcripts markedly increased within the first day after lesion and then steadily decreased for at least 4 weeks. CRII‐7/rMDC15 mRNA expression was further examined during postnatal development and maturation of rat sciatic nerve and brain, as well as in cultured Schwann cells, meningeal fibroblasts, and astrocytes. In situ hybridization on paraffin sections showed the cellular localization of CRII‐7/rMDC15 mRNA in Schwann cells and endothelial cells of peripheral nerve and in various neuronal populations in brain and spinal cord. GLIA 32:313–327, 2000. © 2000 Wiley‐Liss, Inc.

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