scholarly journals Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

2007 ◽  
Vol 204 (11) ◽  
pp. 2603-2614 ◽  
Author(s):  
Hal Blumberg ◽  
Huyen Dinh ◽  
Esther S. Trueblood ◽  
James Pretorius ◽  
David Kugler ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Inflammatory Cell ◽  
Family Members ◽  
Skin Inflammation ◽  
Antagonistic Activity ◽  
Psoriatic Skin ◽  
Inflammatory Cell Infiltrate ◽  
Skin Abnormalities

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.

scholarly journals An important role of lymphatic vessel activation in limiting acute inflammation

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4667-4678 ◽  
Author(s):  
Reto Huggenberger ◽  
Shoib S. Siddiqui ◽  
Daniela Brander ◽  
Stefan Ullmann ◽  
Kathrin Zimmermann ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Lymphatic Vessel ◽  
Acute Inflammation ◽  
Lymphatic Vessels ◽  
Skin Inflammation ◽  
Ultraviolet B ◽  
Delayed Type Hypersensitivity ◽  
Inflammatory Cell Infiltrate ◽  
Keratin 14

Abstract In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 established models of acute cutaneous inflammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Expression of VEGFR-3 by lymphatic endothelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expression was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu in the inflamed skin of VEGF-C or VEGF-D transgenic mice. However, the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage from the ear skin. These results provide evidence that specific lymphatic vessel activation limits acute skin inflammation via promotion of lymph flow from the skin and reduction of edema formation.

scholarly journals Bacteriocin-like activity of oral Fusobacterium nucleatum isolated from human and non-human primates

1999 ◽  
Vol 30 (4) ◽  
pp. 324-346 ◽  
Author(s):  
Elerson Gaetti-Jardim Júnior ◽  
Mario Julio Avila-Campos
Keyword(s):  
Oral Cavity ◽  
Microbial Ecology ◽  
Dental Plaque ◽  
Fusobacterium Nucleatum ◽  
Antagonistic Activity ◽  
Healthy Individuals ◽  
Bacterial Microbiota ◽  
Reference Strains

Fusobacterium nucleatum is indigenous of the human oral cavity and has been involved in different infectious processes. The production of bacteriocin-like substances may be important in regulation of bacterial microbiota in oral cavity. The ability to produce bacteriocin-like substances by 80 oral F. nucleatum isolates obtained from periodontal patients, healthy individuals and Cebus apella monkeys, was examinated. 17.5% of all tested isolates showed auto-antagonism and 78.8% iso- or hetero-antagonism. No isolate from monkey was capable to produce auto-inhibition. In this study, the antagonistic substances production was variable in all tested isolates. Most of the F. nucleatum showed antagonistic activity against tested reference strains. These data suggest a possible participation of these substances on the oral microbial ecology in humans and animals. However, the role of bacteriocins in regulating dental plaque microbiota in vivo is discussed.

scholarly journals Oocyte-Specific Overexpression of Mouse Bone Morphogenetic Protein-15 Leads to Accelerated Folliculogenesis and an Early Onset of Acyclicity in Transgenic Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2807-2815 ◽  
Author(s):  
Heather E. McMahon ◽  
Osamu Hashimoto ◽  
Pamela L. Mellon ◽  
Shunichi Shimasaki
Keyword(s):  
Transgenic Mice ◽  
Bone Morphogenetic Protein ◽  
Early Onset ◽  
Ovarian Function ◽  
Chimeric Protein ◽  
Mature Protein ◽  
Follicle Growth ◽  
Morphogenetic Protein

Whereas mutations in the bmp15 gene cause infertility in ewes and women due to defects in folliculogenesis, most defects in female mice lacking bone morphogenetic protein (BMP)-15 are confined to the ovulation process, supportive of the observation that functional mouse BMP-15 is barely detected in oocytes in vivo until after the LH surge. In addition, the mouse BMP-15 proprotein is not processed into the functional mature protein in transfected cells. However, a chimeric protein consisting of the human proregion, human cleavage site, and mouse mature region (termed hhmBMP-15) is processed and the mature protein secreted. To study the role of BMP-15 in folliculogenesis, we generated transgenic mice overexpressing hhmBMP-15, exclusively in oocytes during folliculogenesis and confirmed the overexpression of mouse BMP-15 mature protein. Immature transgenic mice exhibited accelerated follicle growth with decreased primary follicles and an increase in secondary follicles. Granulosa cells of immature mice displayed an increased mitotic index and decreased FSH receptor mRNA expression. Adult mice had normal litter sizes but an increased number of atretic antral follicles. Interestingly, aging mice exhibited an early onset of acyclicity marked by increased diestrus length and early occurrence of constant diestrus. These findings indicate the role of BMP-15 in vivo in promoting follicle growth and preventing follicle maturation, resulting in an early decline in the ovarian reserve of transgenic mice. Therefore, the lack of mouse BMP-15 during early folliculogenesis in the wild-type mice may be relevant to their polyovulatory nature as well as the preservation of ovarian function as the mice age.

scholarly journals Role of c-Fos in orthodontic tooth movement: an in vivo study using transgenic mice

2020 ◽  
Author(s):  
Maximilian G. Decker ◽  
Cita Nottmeier ◽  
Julia Luther ◽  
Anke Baranowsky ◽  
Bärbel Kahl-Nieke ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tooth Movement ◽  
Orthodontic Tooth Movement ◽  
In Vivo Study

scholarly journals The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins

2009 ◽  
Vol 186 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Delphine Mérino ◽  
Maybelline Giam ◽  
Peter D. Hughes ◽  
Owen M. Siggs ◽  
Klaus Heger ◽  
...  
Keyword(s):  
Family Members ◽  
Binding Specificity ◽  
In Vitro Studies ◽  
Genetic Approach ◽  
Activation Model ◽  
Bh3 Domain ◽  
Indirect Activation

Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.

In vivo role of caspases in excitotoxic neuronal death: generation and analysis of transgenic mice expressing baculoviral caspase inhibitor, p35, in postnatal neurons

2002 ◽  
Vol 108 (1-2) ◽  
pp. 18-32 ◽  
Author(s):  
Masanori Tomioka ◽  
Keiro Shirotani ◽  
Nobuhisa Iwata ◽  
Hahn-Jun Lee ◽  
Fusheng Yang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neuronal Death ◽  
Caspase Inhibitor ◽  
Excitotoxic Neuronal Death

scholarly journals Nrf Transcription Factors in Keratinocytes Are Essential for Skin Tumor Prevention but Not for Wound Healing

2006 ◽  
Vol 26 (10) ◽  
pp. 3773-3784 ◽  
Author(s):  
Ulrich auf dem Keller ◽  
Marcel Huber ◽  
Tobias A. Beyer ◽  
Angelika Kümin ◽  
Christina Siemes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Wound Repair ◽  
Target Genes ◽  
Dominant Negative ◽  
Skin Tumor ◽  
Cellular Stress Response ◽  
Skin Development

ABSTRACT The Nrf2 transcription factor is a key player in the cellular stress response through its regulation of cytoprotective genes. In this study we determined the role of Nrf2-mediated gene expression in keratinocytes for skin development, wound repair, and skin carcinogenesis. To overcome compensation by the related Nrf1 and Nrf3 proteins, we expressed a dominant-negative Nrf2 mutant (dnNrf2) in the epidermis of transgenic mice. The functionality of the transgene product was verified in vivo using mice doubly transgenic for dnNrf2 and an Nrf2-responsive reporter gene. Surprisingly, no abnormalities of the epidermis were observed in dnNrf2-transgenic mice, and even full-thickness skin wounds healed normally. However, the onset, incidence, and multiplicity of chemically induced skin papillomas were strikingly enhanced, whereas the progression to squamous cell carcinomas was unaltered. We provide evidence that the enhanced tumorigenesis results from reduced basal expression of cytoprotective Nrf target genes, leading to accumulation of oxidative damage and reduced carcinogen detoxification. Our results reveal a crucial role of Nrf-mediated gene expression in keratinocytes in the prevention of skin tumors and suggest that activation of Nrf2 in keratinocytes is a promising strategy to prevent carcinogenesis of this highly exposed organ.

scholarly journals Kidney osteoclast factors and matrix metalloproteinase expression in a mice model of diet-induced obesity and diabetes

2019 ◽  
Author(s):  
Francine dos Santos-Macedo ◽  
Bianca Martins-Gregorio ◽  
Elan Cardozo Paes-de-Almeida ◽  
Leonardo de Souza Mendonça ◽  
Rebeca de Souza Azevedo ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Renal Tissue ◽  
Inflammatory Cell Infiltrate ◽  
Mice Model ◽  
Diet Induced Obesity ◽  
Obesity And Diabetes ◽  
Underlying Mechanisms ◽  
Mononuclear Inflammatory Cell ◽  
High Sucrose

ABSTRACTThe role of RANKL/RANK/OPG system on bone remodeling is well known, and there is evidence that it is also important to cardiovascular and kidney pathology, although the underlying mechanisms are not elucidated so far. Thus, we investigated in a mice model of diet-induced obesity and diabetes if renal histopathological changes are associated with the expression of RANKL/RANK/OPG system and matrix metalloproteinases (MMPs). Three months old C57BL/6 mice were fed with control (AIN93M) or high-fat high sucrose (HFHS) diets for 21 weeks (CEUA/UFF #647/15). The HFHS group showed weight gain (+35%, P=0.0001), increased epididymal, inguinal and retroperitoneal fat pad weight (+121 %, P = 0.0006; +287 %, P = 0.0007 and; +286 %, P < 0.0001, respectively), and hyperglycemia (+43%, P=0.02). The kidney of some HFHS fed mice displayed mononuclear inflammatory cell infiltrate (40%), perivascular fibrosis (20%), and focal tubule mineralization (20%). Glomeruli hypertrophy was not detected. Unexpectedly, OPG, RANK, MMP-2 and MMP-9 expression was not altered in HFHS groups (Western blot analysis). In conclusion, the expression of RANKL/RANK/OPG system proteins and MMPs was not influenced by diet-induced obesity and diabetes in the kidney of male C57BL/6 mice, although some adverse histopathological remodeling is noticed in the renal tissue.

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