Cachexia and graft-vs.-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice.
TL;DR: The results suggest that TNFalpha expression by keratinocytes not only plays a role in inflammatory and graft-versus-host-disease-like responses in the skin, but also in other tissues, apparently by virtue of stratified squamous epithelial-derived TNF alpha entering the bloodstream.
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Abstract: Tumor necrosis factor alpha (TNF alpha) orchestrates a wide range of effects that combat severe infections in animals. At lower levels, TNF alpha plays an important protective role in stimulating chemotaxis and antimicrobial activity of neutrophils, macrophages, and eosinophils. During chronic illness, TNF alpha secretion can be elevated markedly, giving rise to cachexia, hemorrhage, necrosis and, ultimately, death. Although TNF alpha may mediate many of its effects through macrophages, 30% of TNF alpha injected into animals concentrates in the skin. In recent years, it has been shown that keratinocytes can be induced to synthesize TNF alpha. To explore the role of TNF alpha synthesis in keratinocytes, we used a keratin-14 (K14) promoter to target human TNF alpha expression in the epidermis and other stratified squamous epithelia of transgenic mice. Most mice expressing the K14-TNF alpha transgene stopped gaining weight within 1 week postbirth, and exhibited retarded hair growth. In the skin, adipose production was profoundly inhibited, whereas signs of fibrosis and immune infiltration were evident in the dermis. Over time, the epidermis exhibited an increased stratum corneum, as signs of necrosis began to appear in the skin. Within 3-5 weeks, the mice displayed features characteristic of cachexia and necrosis. Our results suggest that TNF alpha expression by keratinocytes not only plays a role in inflammatory and graft-versus-host-disease-like responses in the skin, but also in other tissues, apparently by virtue of stratified squamous epithelial-derived TNF alpha entering the bloodstream. Our results have enabled the first evaluation of many of the effects of TNF alpha in transgenic animals.
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Citations
Glutathione Regulation of Tumor Necrosis Factor-α-Induced NF-κB Activation in Skeletal Muscle-Derived L6 Cells☆
Chandan K. Sen,Chandan K. Sen,Savita Khanna,Savita Khanna,Abraham Z. Reznick,Abraham Z. Reznick,Sashwati Roy,Sashwati Roy,Lester Packer +8 more
TL;DR: Results from G SSG reductase inhibited cells suggest that GSSG may participate in, but is not required for, TNFα induced NF-κB activation, and the involvement of reactive oxygen species in this activation system seems likely.
Influence of IN-1 antibody and acidic FGF-fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts
James D. Guest,Donald H. Hesse,Lisa Schnell,Martin E. Schwab,Mary Bartlett Bunge,Richard P. Bunge +5 more
TL;DR: Human SC grafts alone do not support the regeneration of injured CST fibers and do not prevent die‐back, but grafts plus IN‐1 antibody‐containing supernatant support some sprouting but die‐ back continues, and graftsplus aFGF‐fibrin glue support regeneration of some fibers into the grafts and reduce die‐backs.
Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB
TL;DR: Stratified epithelium contains a mitotically active basal layer of cells that cease proliferating, then migrate outwards and undergo terminal differentiation, and NF-κB activation in this tissue, in contrast to its role in other settings, is important for cellular growth inhibition.
•Journal Article
Targeted expression of activated erbB-2 to the epidermis of transgenic mice elicits striking developmental abnormalities in the epidermis and hair follicles.
TL;DR: It is demonstrated that the skin is sensitive to erbB-2 signaling, suggesting an important role for this receptor tyrosine kinase in epidermal growth, differentiation, and hair follicle morphogenesis.
Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants.
Martina Buck,Mario Chojkier +1 more
TL;DR: The decreased body weight, muscle wasting and skeletal muscle molecular abnormalities of cachexia were prevented by treatment of TNF alpha mice with the antioxidants D‐alpha‐tocopherol of BW755c, or the NOS inhibitor nitro‐L‐arginine.
References
An endotoxin-induced serum factor that causes necrosis of tumors
TL;DR: It is proposed that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.
4.8K
Shock and tissue injury induced by recombinant human cachectin.
Kevin J. Tracey,Bruce Beutler,Stephen F. Lowry,James P Merryweather,Stephen D. Wolpe,Ian W. Milsark,Robert J. Hariri,Thomas J. Fahey,Alejandro Zentella,J. D. Albert,G. Tom Shires,Anthony Cerami +11 more
TL;DR: It appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.
2.7K
Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia
Kevin J. Tracey,Kevin J. Tracey,Yuman Fong,David G. Hesse,Kirk R. Manogue,Annette T. Lee,George C. Kuo,Stephen F. Lowry,Anthony Cerami +8 more
TL;DR: Protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion, indicating that cachectin is a mediator of fatal bacteraemic shock and suggesting that antibodies against Cachectin offer a potential therapy of life-threatening infection.
2.7K
Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF).
TL;DR: With IL 6 transgenic mice, deregulation of the IL 6 expression was suggested to be involved in the generation of plasmacytoma/myeloma and mesangium proliferative glomerulonephritis and the findings suggest the presence of a positive regulatory loop in acute‐phase reaction.
1.3K
Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin
John R. Gordon,Stephen J. Galli +1 more
TL;DR: Evidence is presented that resident mouse peritoneal mast cells constitutively contain large amounts of TNF-α bioactivity, whereas cultured, immature mast cells vary in their T NF-α content, and that release of TTF-α by mast cells may contribute to host defence, the pathophysiology of allergic diseases and other processes dependent on TFB.
1K
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