Macrophages are supposed to play a key role in inflammatory and tumor angiogenesis. Their importance derives from (1) their ubiquitous presence in normal and especially inflamed tissues, (2) their potential to become activated in response to appropriate stimuli, and (3) their repertoire of secretory products. By release of proteases, growth factors (bFGF, GM-CSF, TGF-alpha, IGF-I, PDGF, VEGF/VPF, TGF-beta), and other monokines (IL-1, IL-6, IL-8, TNF-alpha, substance P, prostaglandins, interferons, thrombospondin 1), activated macrophages have the capability to influence each phase of the angiogenic process, such as alterations of the local extracellular matrix, induction of endothelial cells to migrate or proliferate, and inhibition of vascular growth with formation of differentiated capillaries. This review describes macrophage physiology and the influence of macrophage secretory products on the different phases of angiogenesis in vitro and in vivo.

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Irradiation with ultraviolet (UV) B radiation results in the formation of apoptotic keratinocytes called sunburn cells. Recently, it was demonstrated that keratinocytes can release tumor necrosis factor-alpha (TNF-alpha), which is known to cause apoptosis in particular cells. In addition, it has been shown that UVB light induces the release of TNF-alpha by keratinocytes and that keratinocytes express the 55-kD receptor for TNF-alpha. Therefore, we investigated whether TNF-alpha is involved in UV-induced apoptosis of keratinocytes. Normal human keratinocytes and HaCaT cells were exposed to UVB light, and apoptosis was examined by nick translation evaluated by fluorescence-activated cell sorter analysis. UVB induced apoptosis in a dose-dependent manner, which was confirmed by electron microscopy. Addition of a polyclonal antibody directed against human TNF-alpha immediately after UVB exposure was able to reduce DNA fragmentation. However, it was not possible to rescue all cells from apoptosis. To prove whether TNF-alpha is also involved in vivo in UVB-induced apoptosis of keratinocytes, Balb/c mice were exposed to UVB on their abdomens, skin biopsies were performed 24 h later, and sunburn cells were counted. A single dose of 2000 J/m2 caused a significant induction of sunburn cells. Subcutaneous injection of a polyclonal antibody directed against murine TNF-alpha immediately after UVB treatment resulted in a significant but incomplete reduction of sunburn cells, whereas injection of a rabbit IgG as a control had no effect. In both the in vitro and in vivo systems, application of recombinant TNF-alpha alone either to untreated keratinocytes or into normal murine skin did not induce sunburn cells. Thus, these data demonstrate that TNF-alpha is involved in UVB-induced apoptosis, but by itself is not able to induce sunburn cells. This further supports the notion that UVB-induced apoptosis of keratinocytes is a multifactorial event.

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Proopiomelanocortin (POMC) is known to be synthesized in the pituitary gland and is subsequently cleaved by specific prohormone convertases into biologically active peptide hormones such as melanocyte stimulating hormones (MSH), adrenocorticotropin (ACTH) and endorphins (EP). Guanine nucleotide-binding protein (G-protein)-coupled receptors, which have only recently been discovered, are involved in the transmission of their message. There is also evidence indicating that POMC is not only produced by pituitary cells but is an ubiquitous molecule, that is cleaved cell- and tissue-specific. It has also been shown that the epidermis keratinocytes as well as melanocytes express POMC upon stimulation and release alpha MSH and ACTH. In addition to their function as hormones, POMC peptides have been shown to exert a variety of immunoregulatory effects by modulating the function of immunocompetent cells as well as cytokines. These findings provide further evidence for the immunoneuroendocrine network playing a crucial role during the pathogenesis of immune and inflammatory skin disease.

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The carcinoembryonic antigen (CEA) family comprises a group of glycoproteins including the classical CEA, nonspecific cross-reacting antigens (NCA), and biliary glycoprotein (BGP). CEA glycoproteins have been identified in many glandular and mucosal tissues. In view of their putative role in cell adhesion, protein sorting, and signal transduction, CEA glycoproteins are thought to be involved in embryogenesis, architectual integrity, and secretory mechanisms of glandular epithelia. Since there are few data available on the expression of CEA-like proteins in human skin, the aim of this study was to immunohistochemically specify and localize the CEA glycoproteins in cutaneous adult and fetal glands using a panel of well-characterized antibodies. The secretory parts of eccrine sweat glands expressed CEA, NCA-90, and BGP, whereas apocrine glands remained unreactive for CEA glycoproteins. The ductal epithelia of both eccrine and apocrine glands contained CEA and NCA-90. Sebaceous glands were stained for BGP only. Electron microscopy of sweat glands showed CEA glycoprotein expression in cytoplasmic organelles and on microvilli lining the ductal surface. In sebaceous glands, BGP were demonstrated in small vesicles and along the cell membranes of differentiating sebocytes. Fetal development of cutaneous glands was associated with early expression of CEA glycoproteins. Additionally, mice transgenic for human CEA were shown to express CEA in sweat glands. The overall distribution of CEA glycoproteins in cutaneous glands was consistent with that in epithelia of other glandular tissues.

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