Th17, a culprit in psoriasis
Etanercept, a fusion between tumor necrosis factor (TNF) receptor and immunoglobulin, has been used to block TNF for the treatment of psoriasis, an autoimmune disease that affects 1–2% of the population in North America and Europe. Zaba and colleagues recently demonstrated that psoriasis disease improvement following etanercept treatment correlated with decreases in dendritic cell and Th17 cell products and effector molecules in the early weeks, whereas final disease resolution was associated with late downregulation of Th1 cells after several months. Specifically, etanercept acts early to inhibit inflammatory dendritic cell maturation and cytokine production. Ultimately, this modulation leads to decreased Th17 cell function. Although Th17 cells may drive keratinocyte hyperplasia and inflammatory cytokine production, Th1 cells still appear to be critical for leukocyte activation and sustaining interferon-
signaling pathways. Additional research is necessary to tease out the precise roles of Th1 and Th17 cells in psoriasis. (J Exp Med 204:3183–94, 2007)
The cycles of hair regeneration
Cyclic activation of hair stem cells in the follicle bulge facilitates regeneration throughout adult life. Recently, Plikus and colleagues described periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 with low expression during early propagating anagen and high expression during late autonomous anagen. The dermal macroenvironment was implicated as the source of periodic Bmp2 and Bmp4 expression. Reduction of BMP signaling in transgenic mice reduced the period of refractory telogen, and delivery of BMP protein converted competent telogen tissue to refractory in normal mice. Interestingly, transplantation of skin from mice overexpressing a BMP antagonist onto a wild-type host animal implicated both donor and host follicles in cycling and indicated that the deciding force was overall BMP equilibrium. These results suggest that BMPs may be the elusive "chalone" inhibitors of anagen development that researchers hypothesized more than 50 years ago. (Nature 451:340–4, 2008)
Melanoma initiator uncovered
Cells responsible for tumor initiation and tumor growth have been described in human hematological malignancies as well as in solid tumors. Schatton and colleagues recently identified a subpopulation of cells enriched for initiation of malignant melanoma, and these cells expressed the chemoresistance mediator ABCB5. Human-to-NOD/SCID mouse xenotransplantation studies revealed that ABCB5+ populations resulted in tumor initiation and development. In addition, genetic lineage tracking experiments demonstrated that ABCB5+ cells yielded both ABCB5+ and ABCB5– cells, whereas ABCB5– cells gave rise only to ABCB5– cells. These results tout the self-renewal and differentiation abilities of ABCB5+ cells. Importantly, administration of a monoclonal antibody directed against ABCB5 inhibited tumor growth as well as tumor formation in the nude mouse melanoma xenograft model. Thus, targeting these malignant melanoma-initiating cells may prove to be an important and novel therapeutic strategy that may overcome the common chemoresistance in this type of cancer. (Nature 451:345–9, 2008)
Relay of pain
Innervation of the stratum granulosum of the epidermis occurs via unmyelinated neurons that express the mas-related G-protein-coupled receptor (Mrgprd). Using patch clamp experiments to characterize neurons from mice that express green fluorescent protein concurrently with Mrgprd, Dussor and colleagues revealed that these neurons displayed nociceptor-like characteristics, including small-diameter cell bodies, long-duration action potentials, action potentials with overshoots, Na+ currents that are resistant to tetrodotoxin, and Ca2+ currents that are inhibited by opioids. Moreover, these neurons exhibit currents selectively evoked by extracellular ATP. These Mrgprd+ neurons likely respond to the release of ATP, and possibly other molecules, by epidermal keratinocytes. Keratinocytes may serve as the intermediaries that receive the pain sensations and initiate signaling to the central nervous system via these specific neurons. (J Neurophysiol, published online 30 January 2008; doi:10.1152/jn.01396.2007)
The oncogene paradox
The activated mutant BRAF oncogene BRAFV600E induces uncontrolled proliferation in melanomas, yet causes senescence in benign nevi. Clues into these seemingly contradictory roles of BRAF were recently uncovered when Wajapeyee and colleagues performed a genome-wide RNA interference screen of 28,000 genes to identify factors required for the mutant to block cellular proliferation. Seventeen factors, including the secreted protein insulin growth factor binding protein 7 (IGFBP7), were found to bypass the BRAFV600E-mediated proliferation. IGFBP7 induced senescence and apoptosis via autocrine and/or paracrine feedback. This mechanism is dependent on inhibition of BRAF–MEK–ERK signaling. Loss of IGFBP7 expression is a critical step in the development of a BRAFV600E melanoma, and this loss occurs primarily by epigenetic silencing through hypermethylation of the promoter. Additionally, treatment of these melanomas with recombinant IGFBP7 suppressed tumor growth. Thus, IGFBP7 may prove to be a useful target for treating malignancies harboring activating BRAF mutations. (Cell, 132:363–74, 2008)
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