In this Issue

Abstract

One of the major developments in human biology is the understanding of how release of growth factors and other proteins can be controlled by both local and systemic signals of many types and sources: circulating hormones, cytokines released from lymphocytes and macophages activated by the immune response, cytokines and growth factors from neighboring cells, and neuropeptides released by autonomic and sensory nerves. In the skin, the keratinocytes are a major target of stimulation by hormones, neuropeptides, cytokines, chemokines, and external stimuli such as ultraviolet light, heat, and cold, and control a major part of cutaneous biology through the release of cytokines, chemokines, growth factors, and other types of inflammatory mediators. Nerve growth factor (NGF) is detected in the neurons of the central and peripheral nervous system, and is found in the skin in keratinocytes, endothelial cells, and Langerhans cells. It is believed to be an important factor in neuronal maintenance, survival, and repair in the skin, especially during inflammatory reactions and wound healing. NGF is also an important survival factor for human melanocytes, and may affect melanocyte survival in segmental vitiligo and other pigmentary disorders. In this issue, Burbach et al. (p. 1075) report that the neuropeptides Substance P and Neurokinin A induce transcription of NGF and secretion of bio-active protein from both human and murine keratinocytes. They also demonstrate increases in expression of NGF in murine epidermis exposed to capsaicin, a potent inducer of substance P release. Considering the mass of keratinocytes and the extensive sensory nerve network that serves it, one would conclude that keratinocyte-derived NGF controls innervation in the papillary dermis and melanocyte survival in the epidermis. Activation of neuropeptides may control key responses in wound healing and remodeling of the papillary dermis and dermis, through the transcription and release of keratinocyte NGF. Vascular genesis refers to the process of blood vessel formation during development. Angiogenesis is new vessel formation, in tissue repair or during tumorgenesis. Angiogenesis is a key factor in survival of tumors once they progress past a small initial tumor mass, and inhibition of tumor angiogenesis has been proposed as a new therapeutiuc approach by Folkman and colleagues. Angiogenesis is a highly regulated process with both ‘‘on’' and ‘‘off’' controls, intended to first induce new vessel formation in responses to wounding or other stimuli, and then cause regression of the new vessels when the stimulus is repaired. The ‘‘off’' signal is not effectively applied in primary tumors, which ‘‘hijack’' the angiogenesis process to promote local tumor survival. Angiogenesis is induced by a family of isoforms of vascular endothelial growth factor (VEGF) and a corresponding family of receptors, and by the angiopoeitins and their receptors. In addition, angiogenesis can be controlled by a family of naturally occurring inhibitors of angiogenesis: Thrombospondin-1 and -2, angiostatin (a fragment of plasminogen), and endostatin (a fragment of collagen XVIII). Vasostatin is a 180 amino acid NH2-terminal fragment of human calreticulin that also has potent antiangiogenic activity, and is a candidate for clinical antiangiogenesis trials. In this issue, Lange-Asschenfeldt et al. (p. 1036) used an in vivo murine model to simultaneously study the effects of vasostatin on angiogensis and wound healing. Vasostatin was found to inhibit both tumor growth and angiogenesis in a CA46 Burkitt Lymphoma model. Interesting, the rate of wound healing in these vasostatin-treated animals was not decreased, even though the angiogenic response in the healing wounds was greatly diminished. These results support the hypothesis that malignant tumor growth is more sensitive to inhibition of angiogenesis than is physiologic tissue repair. These findings support an optimistic view that chronic antiangiogenic therapy can be used to selectively reverse tumor vascularity without impairing physiologic tissue repair. Another paper in this issue examines the effects of endogenous antiangiogenic protein on melanoma metastasis, and may even support the view that use of angiogenesis inhibitors is mandatory in large melanomas from which micrometastases may have already spread. Judah Folkman has made the observation that surgical removal of a primary tumor is often followed by increased growth in pre-existing mico-metastases. He has hypothesized that this phenomenon is explained by the fact that the primary tumor secretes large amounts of long-lasting antiangiogenic proteins that inhibit the growth of early distant micrometastases. He proposes that the primary tumor also makes large amounts of angiogenic factors that are locally bound, and short lived, and promote local tumor angiogensis around the large primary tumor. This hypothesis is tested by Rofstad et al. (p. 1042) in a mouse model with existing melanoma tumors derived from cell lines that produced large amounts of the antiangiogenis factor Thrombospondin-1, or a cell line that did not. Tumors that produced large amounts of TSP-1 greatly reduced the experimental establishment of micrometastases, either from the primary tumor or from tail-vein injection. This effect was blocked by simultaneous injection of anbti-TSP-1. A melanoma line negative for TSP-1 produced neo-vascularized lung colonies after venous inoculation in mice with pre-existing tumors, whereas injection of TSP-1 positive cells in mice already bearing tumors from the same cell lines only produced avascular microcolonies with elevated apoptotic activity. This work poses an interesting question: must excision of large melanomas be accompanied by angiogenic inhibitors like TSP-1 to replace the angiogenesis inhibitors secreted by the primary tumor before excision? Spongiosis is a prominent histologic feature of inflammatory skin disorders characterized by widening of the intercellular spaces between keratinocytes accompanied by cellular condensation. In this issue, Trautmann et al. (p. 927) demonstrate that, in eczematous dermatitis, spongiosis is linked to proteolytic cleavage and functional inactivation of E-cadherin which occurs as a consequence of keratinocyte apoptosis. Interestingly, keratinocyte apoptosis and attendant E-cadherin cleavage could be induced in vitro by activated T lymphocytes and was dependent on Fas/CD95 activation. These results provide tantalizing evidence for immune-mediated keratinocyte death, executed by activation of death receptors, as a mechanism for spongiotic changes in the skin. Two papers in this issue show that UVR suppression of delayed-type hypersensitivity may depend on the UVA spectrum, using both specialized light sources and selective sunscreens to show that this type of immune suppression is induced by UVA (more specifically UVAII) and is blocked by sunscreens containing UVA blockers. In this issue, Nghiem et al. (p. 1193) report that solar-simulated radiation applied to immunized mice suppress immunologic memory and elicitation of DTH reaction. UVA sources (320–400 nm) were as effective as solar simulator radiation (290–400 nm), but UVAI sources (340–290 nm) were not effective. The immunosuppressive effect of UVR was blocked by sunscreens that blocked UVA. The authors state that ‘‘sunlight-induced suppression of established immune reactions may serve as a risk factor for increased susceptibility to infectious agents’', and further illustrate the potential role for UVA in melanoma induction and suppression of immune responses to established melanomas. In another article in this issue, Moyal and Fourtanier (p. 1186) demonstrated the roles of UVA in inhibiting DTH reactions in humans. The authors studied established DTH reactions using a panel of recall antigens to which most individuals react. Using both solar simulator and natural outdoor sunlight to inhibit DTH reactions, they showed that this inhibition could be blocked with sunscreens, but only if they contained highly effective UVA sunscreens. The authors state that ‘‘the SPF, an indicator of protection against sunburn, is not an indicator of the protection against the suppression of the elicitation phase of immune response induced by repeated UV exposures’'. They conclude that ‘‘sunscreens with improved UVA protection have a higher immune protection factor (IPF)’'. These papers further illustrate the importance of UVA in induction of immunosuppression in both animal and human models, and raise the spectre of significant adverse effects induced by chronic UVA exposure, resulting in loss of protective immunity to pathogens and loss of response UV-induced melanomas.