Browsing by Subject "cytokines"

Now showing 1 - 5 of 5
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    The Combination of Low Skeletal Muscle Mass and High Tumor Interleukin-6 Associates with Decreased Survival in Clear Cell Renal Cell Carcinoma
    (MDPI, 2020-06-17) Kays, Joshua K.; Koniaris, Leonidas G.; Cooper, Caleb A.; Pili, Roberto; Jiang, Guanglong; Liu, Yunlong; Zimmers, Teresa A.; Medical and Molecular Genetics, School of Medicine
    Clear cell renal carcinoma (ccRCC) is frequently associated with cachexia which is itself associated with decreased survival and quality of life. We examined relationships among body phenotype, tumor gene expression, and survival. Demographic, clinical, computed tomography (CT) scans and tumor RNASeq for 217 ccRCC patients were acquired from the Cancer Imaging Archive and The Cancer Genome Atlas (TCGA). Skeletal muscle and fat masses measured from CT scans and tumor cytokine gene expression were compared with survival by univariate and multivariate analysis. Patients in the lowest skeletal muscle mass (SKM) quartile had significantly shorter overall survival versus the top three SKM quartiles. Patients who fell into the lowest quartiles for visceral adipose mass (VAT) and subcutaneous adipose mass (SCAT) also demonstrated significantly shorter overall survival. Multiple tumor cytokines correlated with mortality, most strongly interleukin-6 (IL-6); high IL-6 expression was associated with significantly decreased survival. The combination of low SKM/high IL-6 was associated with significantly lower overall survival compared to high SKM/low IL-6 expression (26.1 months vs. not reached; p < 0.001) and an increased risk of mortality (HR = 5.95; 95% CI = 2.86–12.38). In conclusion, tumor cytokine expression, body composition, and survival are closely related, with low SKM/high IL-6 expression portending worse prognosis in ccRCC.
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    Driver Mutations in Leukemia Promote Disease Pathogenesis through a Combination of Cell-Autonomous and Niche Modulation
    (Elsevier, 2020-07-14) Ramdas, Baskar; Mali, Raghuveer Singh; Palam, Lakshmi Reddy; Pandey, Ruchi; Cai, Zhigang; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Kapur, Reuben; Pediatrics, School of Medicine
    Studies of patients with acute myeloid leukemia (AML) have led to the identification of mutations that affect different cellular pathways. Some of these have been classified as preleukemic, and a stepwise evolution program whereby cells acquire additional mutations has been proposed in the development of AML. How the timing of acquisition of these mutations and their impact on transformation and the bone marrow (BM) microenvironment occurs has only recently begun to be investigated. We show that constitutive and early loss of the epigenetic regulator, TET2, when combined with constitutive activation of FLT3, results in transformation of chronic myelomonocytic leukemia-like or myeloproliferative neoplasm-like phenotype to AML, which is more pronounced in double-mutant mice relative to mice carrying mutations in single genes. Furthermore, we show that in preleukemic and leukemic mice there are alterations in the BM niche and secreted cytokines, which creates a permissive environment for the growth of mutation-bearing cells relative to normal cells.
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    The Effects of Human Amniotic Fluid on Periodontal Ligament Fibroblast Cell Viability, Proliferation, and Cytokine/Growth Factor Expression
    (Wolters Kluwer, 2019) Ibraheem, Ahmed Gamil; Blanchard, Steven B.; Al-Hijji, Saleh Mohammed; Al-Nasr-Allah, Khaled; Windsor, L. Jack; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Background: The importance of the amniotic fluid (AF) to the fetus is clear. However, very few studies have been published to examine the potential uses of this fluid in various areas such as tissue regeneration. AF contains epidermal growth factor, transforming growth factor-alpha, transforming growth factor beta-1, insulin-like growth factor-I, erythropoietin and granulocyte colony-stimulating factor, as well as hyaluronic acid and hyaluronic acid-stimulating factor. Previous studies suggest that AF can increase fibroblast proliferation and chemotaxis, and decrease apoptosis as well as promote wound healing. Furthermore, evidence showed that human AF inhibits hyaluronidase, elastase, and cathepsin. The current study examined the effects of human AF on periodontal ligament fibroblasts (PDLF) in terms of cell toxicity, cell proliferation, and cytokine/growth factor expression. Materials and Methods: Cytotoxicity of AF on PDLF was determined using lactate dehydrogenase assays. PDLF proliferation was determined using water-soluble tetrazolium-1 assays. Cytokine/growth factor expression was determined on AF-treated PDLF, AF alone, and PDLF alone utilizing protein arrays. Results: Human AF at 10% and below did not affect cell growth and was not toxic. AF-treated PDLF cells showed a decrease in cytokine/growth factor levels compared to the sum of cytokine/growth factor levels in AF only and cells only for 39 of the 80 proteins examined (48.8%). Of the 39 examined cytokines, 20 inflammatory cytokines, 11 cell cycle cytokines, 1 anti-inflammatory cytokine, and 7 other cytokines were decreased. Conclusion: Human AF at the examined concentrations was not toxic to PDLF cells and did not influence their proliferation. In addition, AF (10%) caused a decrease in the total protein levels of cytokines/growth factors expressed in 39 of the 80 proteins examined (48.8%). Of the 39 examined cytokines, 20 inflammatory cytokines, 11 cell cycle cytokines, 1 anti-inflammatory cytokine, and 7 other cytokines were decreased.
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    Regulation of articular chondrocyte catabolic genes by growth factor interaction
    (Wiley, 2019-02-27) Shi, Shuiliang; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.; Orthopaedic Surgery, School of Medicine
    Osteoarthritis is characterized by a loss of articular cartilage homeostasis in which degradation exceeds formation. Several growth factors have been shown to promote cartilage formation by augmenting articular chondrocyte anabolic activity. This study tests the hypothesis that such growth factors also play an anti-catabolic role. We transferred individual or combinations of the genes encoding insulin- like growth factor I, bone morphogenetic protein-2, bone morphogenetic protein-7, transforming growth factor-β1 and fibroblast growth factor-2, into adult bovine articular chondrocytes and measured the expression of catabolic marker genes encoding A disintegrin and metalloproteinase with thrombospondin motifs-4 and −5, matrix metalloproteinases-3 and −13, and interleukin-6. When delivered individually, or in combination, these growth factor transgenes differentially regulated the direction, magnitude and time course of expression of the catabolic marker genes. In concert, the growth factor transgenes regulated the marker genes in an interactive fashion that ranged from synergistic inhibition to synergistic stimulation. Synergistic stimulation prevailed over synergistic inhibition, reaching maxima of 15.2-fold and 2.7-fold, respectively. Neither the magnitude nor the time course of the effect of the transgene combinations could be predicted on the basis of the individual transgene effects. With few exceptions, the data contradict our hypothesis. The results demonstrate that growth factors that are traditionally viewed as chondrogenic tend also to promote catabolic gene expression. The competing actions of these potential therapeutic agents add an additional level of complexity to the selection of regulatory factors for restoring articular cartilage homeostasis or promoting repair.
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    STAT PROTEIN REGULATION OF FOXP3 EXPRESSION AND INFLAMMATORY CYTOKINE PRODUCTION IN T HELPER CELL SUBSETS
    (2009-03-19T19:00:06Z) O'Malley, John Thomas; Kaplan, Mark H.; Blum, Janice S.; Clapp, D. Wade; Travers, Jeffrey B.
    The differentiation of naïve CD4+ T cells into subsets of T helper cells (Th) is an essential process that impacts host defense and the pathogenesis of immunemediated diseases. Signal transducers and activators of transcription (STAT) proteins, activated downstream of instructive cytokines, dictate and perpetuate the lineage decision of Th cells through both positive and negative effects. This is accomplished by regulating transcription factors, surface receptors and promoting epigenetic changes in gene expression through chromatin remodeling. Transforming growth factor-β1 (TGF-β1) can induce Foxp3 in developing Th cells and these Foxp3-expressing adaptive T regulatory cells (aTregs) are able to suppress inflammation in vitro and in vivo. To define the mechanism by which STAT proteins regulate Th cell pro- and anti-inflammatory phenotypes, we examined T cells deficient in Stat3, Stat4, and Stat6 as well as T cells expressing two STAT4 isoforms after being cultured in the presence or absence of TGF-β1 and cytokines known to be instructive in Th cell development. The negative effects of STAT proteins are demonstrated by our results indicating STAT3, STAT4 and STAT6 proteins activated downstream of the instructive cytokines IL- 6, IL-12 and IL-4, respectively, negatively regulate the development of TGF-β induced Foxp3 and aTreg development. STAT3, STAT4, and STAT6 utilize a vi Mark H. Kaplan, Ph.D., Chair common mechanism to inhibit aTreg generation by inhibiting STAT5, a positive regulator of Foxp3 expression, from binding to the Foxp3 gene. STAT proteins positively effecting inflammatory immunity are demonstrated by our analysis of STAT4 isoforms and their ability to regulate the production of proinflammatory cytokines downstream of IL-12. STAT4β, a STAT4 splice isoform that lacks a Cterminal domain, and STAT4α, a full-length isoform are both capable of mediating inflammatory cell development. However, STAT4β promotes greater inflammation in vivo than STAT4α independent of its ability to repress Foxp3. Instead, the inflammation correlates with STAT4 isoform-dependent expression of inflammatory cytokines. Thus, cytokine-stimulated STAT proteins orchestrate T helper cell pro- and anti-inflammatory cell phenotypes.