Nuclear factor-κB, a ubiquitous transcription factor involved in inflammatory and immune responses, is inappropriately activated in several immuno-related diseases, such as allograft rejection, or ...bronchial asthma. As nuclear factor-κB activity is regulated by inhibitor of κB (IκB), the gene encoding IκB-α was disrupted in mice to observe the in vivo effects of hyperactivation of nuclear factor-κB. IκB-α–/– mice have constitutive nuclear factor-κB activity, severe skin disease, and neonatal lethality. To determine the role of IκB-α deficient immunocytes in the pathogenesis of the skin disease in adult mice, we utilized the RAG2-deficient blastocyst complementation system to generate RAG2–/–, IκB-α–/– chimeras. These animals display a psoriasiform dermatitis characterized by hyperplastic epidermal keratinocytes and dermal infiltration of immunocytes, including lymphocytes. Skin grafts transferred from diseased chimeras to recipient nude mice produce hyperproliferative psoriasiform epidermal keratinocytes in response to stimulation. Furthermore, adoptive transfer of lymph node cells from diseased chimeras to RAG2–/– recipient mice recapitulates the disease. Taken together, these characterizations provide evidence to suggest that constitutive activation of nuclear factor-κB, due to deficiency in IκB-α, can invoke severe psoriasiform dermatitis in adult mice.
The abnormal growth and differentiation in psoriasis is reflected in the abnormal regulation of Epidermal Growth Factor/Transforming Growth Factor Alpha (EGF/TGFα) receptor metabolism. In psoriasis ...and other hyperproliferative skin conditions these receptors are persistently expressed throughout the interfollicular epidermis as long as the growth stimulatory signal persists. One of the first biochemical signs of effective therapy of psoriasis is the return of the EGF/TGFα receptor pattern toward the primarily basilar distribution seen in normal human adult skin. Whether the abnormal expression of TGFα in the involved skin induces the persistent expression of EGF receptors is not known nor is the signal that causes the increased production of TGFα. Studies to determine what factors regulate EGF receptor expression and TGFα induction may yield important new insights into the pathogenesis and therapy of psoriasis.
The embryogenesis of normal human skin is a complex process involving multiple cell types and developmentally regulated growth factors. The immunohistochemical localization of epidermal growth factor ...receptors (EGF-R) was studied in human fetal skin because this receptor modulates all known actions of EGF and TGF-α. EGF-R are present in developing skin as early as the 42nd day of gestation. Immunoreactive EGF-R are present in keratinocytes, endothelial, and skeletal muscle cells. In contrast to normal adult human skin in which the EGF-R are primarily restricted to the basal and immediately suprabasal keratinocytes, the fetal epidermis showed a persistent expression of EGF-R in all cell layers. The absence of EGF-R on the outer, apical surface of periderm cells that are exposed to amniotic fluid was unexpected and may reflect down-regulation of EGF-R by EGF/TGF-α or related fetal growth factors present in amniotic fluid. The complex regulation of EGF-R in embryonic hair follicles and sebaceous glands indicates an active and perhaps regulatory role for EGF/TGF-α in the development and function of pilosebaceous glands as well as mammalian skin in general.
Alzheimer's disease (AD) is characterized neuropathologically by the presence of neuritic plaques (NP) in cerebral cortex and hippocampus, as well as intraneuronal neurofibrillary tangles and ...granulovacuolar degeneration. The etiology of plaque formation has remained obscure, but morphologically NP are known to contain amyloid cores surrounded by astrocytes and degenerating neurons. Although growth factors are important in growth, differentiation and regrowth in response to injury, studies relating growth factors to AD have been lacking. Epidermal growth factor (EGF) plays an important role outside the central nervous system (CNS) through interaction with its specific receptor, EGF-R. Using an antibody to EGF-R (three-step immunoperoxidase staining) in conjunction with fluorescence staining, we found that the majority of NP from patients with pathologically confirmed AD as well as those few NP in the normal aging brain showed intense EGF-R immunoreactivity. Specific staining was seen at the periphery of plaques but not in the central amyloid core. Tissue sections from AD cases were also reacted with antibodies to both glial fibrillary acidic protein (GFAP) and paired helical filaments (PHF) in an attempt to identify which component of the NP was reactive for EGF-R. The antibody to PHF densely stained the periphery of NP but not the central core in a majority of NP. The antibody to GFAP stained a few reactive astrocytes that bordered plaques in only a small proportion of all plaques present. We conclude that the neuron and its processes although not exclusively may be the site of EGF-R immunoreactivity. An EGF/EGF-R system within the CNS may play an important part in scar formation in response to neuronal injury and death or it may function as a trophic factor important in axonal or dendritic sprouting. It is also possible that EGF could serve as a neurotransmitter/neuromodulator in the CNS.
Catfish spine envenomations can result in debilitating hand problems. Virulent bacteria may be introduced through a puncture wound. An offending organism may be difficult to culture, and a foreign ...body may be missed unless there is a high index of suspicion. The majority of cases present early and symptoms resolve within 3 months. We report a markedly delayed presentation and treatment of a catfish “finning” injury that resulted in chronic tenosynovitis to the hand. A review of the literature and current treatment recommendations are provided.
Epidermal growth factor receptors (EGF-Rs) are elevated in active human psoriatic lesions, but decrease in resolving lesions. Similar biologic responses in EGF-R levels have been demonstrated within ...human psoriatic skin grafted onto mice. We tested the hypothesis that flaky-skin mice (fsn/fsn), one proposed genetic animal model of psoriasis, would display EGF-R levels comparable to human psoriatic epidermis and show similar biologic responses. EGF-R levels were characterized in unperturbed sites in fsn/fsn skin and +/? skin by enzyme-linked immunosorbent assay, 125I-EGF binding, and immunostaining. Altered EGF-R levels were noted after mild trauma (tape stripping) or under resolving conditions (30 doses of 50 mJ/cm2 ultraviolet B, 2.5mg/kg oral cyclosporin A, or daily 30 μg/ml topical EGF). Increased EGF-R immunostaining was observed in involved flaky epidermal sites before treatment. To determine whether a hyperproliferative (Koebner) reaction could be induced, we tape stripped fsn/fsn tail and non-flaky dorsal sites. EGF-R levels in dorsal epidermis increased by days 3–4 after injury by enzyme-linked immunoabsorbent assay methods. When fsn/fsn mice received one of three different treatments for 6weeks, the skin returned to a normal phenotype both grossly and microscopically. Immunoreactive EGF-R in treated, but not untreated, sites decreased to either normal or nondetectable levels. These data indicate that fsn/fsn mice exhibit an EGF-R profile identical to that of lesional and nonlesional human psoriatic epidermis. Modulations of the flaky phenotype in response to injury and three different treatments suggest that fsn/fsn is a useful in vivo model for examining new treatment modalities for psoriasiform skin diseases.
Epidermal growth factor receptors (EGF/R) have been reported to be absent in melanomas or, in contrast, to be markers for potential malignancy in melanocytic lesions.
Our purpose was to evaluate the ...literature discrepancies regarding the presence of EGF/R in melanocytic lesions and to determine whether EGF/R presence correlates with the potential for malignancy of melanocytic lesions.
An EGF/R-specific polyclonal antibody was used to study melanomas, dysplastic nevi, congenital nevi, and nevocellular nevi.
All melanocytic cell types (nevus and melanoma cells) in the lesions studied had immunoreactive EGF/R. EGF/R immunoreactivity was also observed throughout the epidermal basal to granular cell layers overlying the melanocytic lesions, although dermal fibroblasts were negative.
The pattern of increased immunoreactive EGF/R in both benign and malignant nevocellular lesions suggests that although EGF/R are not a specific marker of potential malignancy in melanocytic lesions, they may mediate or coordinate growth of keratinocytes and nevus cells.
Degradative events in remodeling connective tissues are mediated through the actions of one or more members of the matrix metalloproteinase family. Conversely, members of the tissue inhibitors of ...metalloproteinase (TIMP) family act to attenuate proteolysis. Because collagenase and TIMP are rapidly secreted into the extracellular matrix following their biosynthesis and may not remain near their cell of origin, we undertook an immunohistochemical examination of human burn injuries to establish the distribution of these proteins during acute wound repair. immunostaining for collagenase and TIMP was markedly increased within the wound bed but not in adjacent regions of histologically normal skin. Immunoreactive collagenase was first noted at the eschar-dermal interface by day 3 after injury and became very prominent in the dermis from day 5 to day 17. By day 5, focal patches of immunoreactive collagenase were found at the epidermal-dermal junctions at the wound margins. Within the wound bed, intense staining for collagenase was noted in the connective tissue surrounding the surviving epithelial appendages and around blood vessels. Immunoreactive TIMP was detected by day 2 both in the dermis and the overlying eschar but rapidly assumed the same interfacial pattern as described for collagenase. Staining for TIIMP was only sporadically found at the dermal-epidermal margins and surrounding surviving epithelial appendages. Like collagenase, TIMP was prominently localized about vascular structures. These studies demonstrate that, in acute wounds, immunoreactive collagenase and TIMP are generally increased throughout the area of injury but particularly so at interface zones including eschar-dermis, epidermis-dermis, appendages-dermis, and around vascular structures.
Amounts and subcellular localizations of 4 protein tyrosine phosphatases (PTPs) were compared in cultured normal human keratinocytes, an immortalized keratinocyte cell line, and 2 squamous cell ...carcinoma (SCC) lines. Cellular localizations for PTPs were determined in biopsies of normal human skin and SCCs. Compared to normal keratinocytes, SCC cell lines had higher levels of PTP‐1B and T‐cell PTP and comparable levels of PTP‐1C or PTP‐1D. The subcellular localization of each PTP was similar in the 3 types of keratinocytes with PTP‐1B localizing to the endoplasmic reticulum, T‐cell PTP exclusively found in the nucleus, PTP‐1C localized to the plasma membrane, cytosol and nucleus, and PTP‐1D present in both cytosol and nucleus. Compared to normal skin, immunoreactive PTP‐1B was markedly increased in the invasive margins of SCCs while T‐cell PTP was generally increased in tumors. PTP‐1C immunostaining varied between cells with no obvious difference between normal and neoplastic tissues. The intensity and distribution of immunoreactive PTP‐1D varied greatly between cells within tumors. These differences in amounts and in cellular and subcellular localization of these PTPs, especially those differences in invasive margins of SCCs, may reflect the diverse roles these PTPs play in the proliferation and invasive potential of neoplastic keratinocytes.
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