Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells and fibroblasts are important constituents of the haemopoietic microenvironment. Growth and function of these cells are controlled by a variety of cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). We analysed the effects of novel tyrosine kinase inhibitors targeting the VEGF and PDGF receptors (compounds SU5614 and SU5768) on the performance of long-term cultures from normal human bone marrow. In developing cultures, the inhibitors induced a dose-dependent reduction in stromal fibroblasts, macrophages and endothelial cells with a concomitant decrease in blood cell production and an increase in fat cells. For SU5614, the concentration inhibiting stroma formation by 50% (IC50) was 123nM, and the IC50 for haemopoietic colony forming cell output was 186 nM. For SU5768, the respective values were 871 nM and 331 nM. Changes in stroma composition and inhibition of haemopoietic cell production were also demonstrable after delayed addition of the inhibitors to established cultures. By contrast, haemopoietic colony formation in clonogenic agar cultures was unimpaired (IC50 not reached at 100 microM). Immunofluorescence studies and time course analyses suggested that the primary effect of the inhibitors was interference with the proliferation and function of fibroblasts and endothelial cells which in turn resulted in decreased haemopoiesis and increased adipogenesis. This was associated with decreased levels in conditioned media of granulocyte-macrophage colony-stimulating factor, interleukin-6 and leptin. VEGF and PDGF may play a hitherto underestimated role in the control of blood cell formation. VEGF/PDGF receptor inhibitors may have therapeutic potential in stroma diseases such as myelofibrosis. Since they weaken the stimulatory signals provided by the microenvironment, they may also be of value in the treatment of leukaemia and other neoplastic bone marrow diseases.
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PMID:Effects of vascular endothelial and platelet-derived growth factor receptor inhibitors on long-term cultures from normal human bone marrow. 1167 6

Cytokines and growth factors are important at each stage of wound healing. This study aims to determine the changing profiles of these factors in intraperitoneal drainage, acute wound fluid, following colorectal surgery, and to correlate levels to wound healing and surgical outcomes. Acute wound fluid samples (n = 52 patients) were collected daily from postoperative day 1 until drain removal. Levels of cytokines (interleukins-6 and -1beta and tumor necrosis factor-alpha) and epidermal growth factor, platelet-derived growth factor, vascular endothelial derived growth factor, basic fibroblast growth factor, and transforming growth factor-beta1 were determined by enzyme-linked immunosorbent assay. A significant negative correlation emerged between the levels of interleukin-6, epidermal growth factor, platelet-derived growth factor, and basic fibroblast growth factor and the postoperative day, e.g., basic fibroblast growth factor : day 1, 695, median (29-2,806, range) pg/ml; day 2, 249 (1-1,784); day 3, 94 (0-722); day 7, 22 (0-326) (p < 0.05, Spearman's correlation). Levels appeared to relate to the stage of wound healing. Several factors, in particular interleukin-1beta and tumor necrosis factor-alpha levels, correlated with surgical outcomes such as the need for a defunctioning stoma and/or postoperative complications. Cytokines and growth factors are involved in normal wound healing, and their levels in acute wound fluid may act as markers of wound healing and surgical outcome.
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PMID:Growth factor profiles in intraperitoneal drainage fluid following colorectal surgery: relationship to wound healing and surgery. 1284 13

Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research-not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed.
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PMID:Emerging targets and novel strategies in the treatment of AIDS-related Kaposi's sarcoma: bidirectional translational science. 1700 5

Recent studies have shown that tissue exudates, such as burn blister fluid and donor site wound fluid, have promotive effects on wound healing. In the present study, results obtained with enzyme-linked immunosorbent assays showed that at least three cytokines, transforming growth factor-beta1, transforming growth factor-alpha, and interleukin-6, exist at high concentrations in burn blister fluids. It was also found that these exudates were able to greatly enhance the rate of human fibroblast proliferation. However, neutralizing antibodies to transforming growth factor-beta1, transforming growth factor-alpha, interleukin-6, and platelet-derived growth factor failed to prevent this proliferative effect. Ultrafiltration of the exudates showed these cytokines to be in the high molecular weight fractions (30 to 300 kDa and >300 kDa) and that these fractions retained mitogenic activity toward fibroblasts. Therefore it was postulated that the cytokines were bound to high molecular weight substances such as serum proteins in these exudates and could escape neutralization by antibodies directed against them.
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PMID:Effects of cytokines in burn blister fluids on fibroblast proliferation and their inhibition with the use of neutralizing antibodies. 1730 93

Skin wound healing is mediated by inflammatory cell infiltration that is highly regulated by various adhesion molecules. Mice lacking intercellular adhesion molecule-1 (ICAM-1) delayed skin wound healing and mice lacking both L-selectin and ICAM-1 (L-selectin/ICAM-1(-/-)) show more delayed wound healing. Deficiency of both endothelial selectins (E-selectin or P-selectin) also delays wound healing. However, the relative contribution and interaction of selectins and ICAM-1 to the wound healing remain unknown. To clarify them, repair of excisional wounds was examined in L-selectin/ICAM-1(-/-) mice, wild-type mice with both E- and P-selectin blockade, and L-selectin/ICAM-1(-/-) mice with both E- and P-selectin blockade. Wild-type mice with both E- and P-selectin blockade showed delayed wound healing that was comparable with that in L-selectin/ICAM-1(-/-) mice. Combined E- and P-selectin blockade in L-selectin/ICAM-1(-/-) mice resulted in more significant delay. Mice lacking or blocked for adhesion molecules also showed suppressed keratinocyte migration, angiogenesis, granulation tissue formation, leukocyte infiltration, and cytokine expression, including transforming growth factor-beta and interleukin-6. Application of basic fibroblast growth factor (bFGF) but not platelet-derived growth factor to the wounds significantly improved wound healing in L-selectin/ICAM-1(-/-) mice with both E- and P-selectin blockade. bFGF significantly increased the leukocyte infiltration and subsequent fibrogenic cytokine production, as well as keratinocyte migration, angiogenesis, and collagen synthesis despite the loss of four kinds of adhesion molecules. These results indicate that skin wound healing is regulated cooperatively by all selectins and ICAM-1 and may provide critical information for the therapy of skin wounds.
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PMID:Endothelial selectins regulate skin wound healing in cooperation with L-selectin and ICAM-1. 1759 78

Wound fluids, human serum from platelet-poor and platelet-rich plasma (SPPP and SPRP), contain various soluble factors involved in cell growth and proliferation. Levels of cytokines, chemokines, and matrix metalloproteinases (MMPs) in drainage fluids (DFs) harvested from subcutaneous wounds, punctured fluids (PF) from seroma, and SPPP were measured. SPPP and SPRP from four healthy volunteers were also subjected to the analysis. Biochemical profiles of DF reflected the sequential stages of wound healing. Early-phase DF contained high concentrations of basic fibroblast growth factor and platelet-derived growth factor and EGF. The levels of keratinocyte growth factor, interleukin-6, and MMP-8 in DF peaked on days 2-3, while vascular endothelial growth factor, hepatocyte growth factor, interleukin-8, and MMP-1 increased over time during days 0-6. Punctured fluids contained high levels of TGF-beta1, keratinocyte growth factor, vascular endothelial growth factor, hepatocyte growth factor, and MMP-1. Experiments using human adipose-derived stem cells and dermal fibroblasts cultured in media containing various concentrations of DF and fetal bovine serum suggested that for some cell types, DF-contained growth factors that are not obtained from SPRP could be used to supplement or substitute for serum in culture media. SPRP and DF are economical ready-made mixtures of serum and autologous soluble factors, and may be differentially useful for regenerative therapies.
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PMID:Characterization of wound drainage fluids as a source of soluble factors associated with wound healing: comparison with platelet-rich plasma and potential use in cell culture. 1765 95

We previously demonstrated that curcumin, a polyphenolic antioxidant purified from turmeric, up-regulated peroxisome proliferator-activated receptor (PPAR)-gamma gene expression and stimulated its signaling, leading to the inhibition of activation of hepatic stellate cells (HSC) in vitro. The current study evaluates the in vivo role of curcumin in protecting the liver against injury and fibrogenesis caused by carbon tetrachloride (CCl(4)) in rats and further explores the underlying mechanisms. We hypothesize that curcumin might protect the liver from CCl(4)-caused injury and fibrogenesis by attenuating oxidative stress, suppressing inflammation, and inhibiting activation of HSC. This report demonstrates that curcumin significantly protects the liver from injury by reducing the activities of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, and by improving the histological architecture of the liver. In addition, curcumin attenuates oxidative stress by increasing the content of hepatic glutathione, leading to the reduction in the level of lipid hydroperoxide. Curcumin dramatically suppresses inflammation by reducing levels of inflammatory cytokines, including interferon-gamma, tumor necrosis factor-alpha, and interleukin-6. Furthermore, curcumin inhibits HSC activation by elevating the level of PPARgamma and reducing the abundance of platelet-derived growth factor, transforming growth factor-beta, their receptors, and type I collagen. This study demonstrates that curcumin protects the rat liver from CCl(4)-caused injury and fibrogenesis by suppressing hepatic inflammation, attenuating hepatic oxidative stress and inhibiting HSC activation. These results confirm and extend our prior in vitro observations and provide novel insights into the mechanisms of curcumin in the protection of the liver. Our results suggest that curcumin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis.
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PMID:Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. 1800 44

The critical role played by stroma-epithelium crosstalk in carcinogenesis and progression of prostate cancer has been increasingly recognized. These interactions are mediated by a variety of paracrine factors secreted by cancer cells and/or stromal cells. In human prostate cancer, reactive stroma is characterized by an increase in myofibroblasts and a corresponding amplification of extracellular matrix production and angiogenesis. Permanent genetic mutations have been reported in stromal cells as well as in tumour cells. Transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor signalling pathways are involved in the process of angiogenesis, whereas hepatocyte growth factor, insulin-like growth factor-1, epidermal growth factor, CXC12 and Interleukin-6 play active roles in the progression, androgen-independent conversion and distal metastasis of prostate cancer. Some soluble factors have reciprocal interactions with androgens and the androgen receptor (AR), and can even activate AR in the absence of the androgen ligand. In this article, we review the complex interactions between cancer cells and the surrounding microenvironment, and discuss the potential therapeutic targets in the stromal compartment of prostate cancer.
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PMID:Stroma-epithelium crosstalk in prostate cancer. 1909 34

Immune cells are critical to the wound-healing process, through both cytokine and growth factor secretion. Although previous studies have revealed that B cells are present within wound tissue, little is known about the role of B cells in wound healing. To clarify this, we investigated cutaneous wound healing in mice either lacking or overexpressing CD19, a critical positive-response regulator of B cells. CD19 deficiency inhibited wound healing, infiltration of neutrophils and macrophages, and cytokine expression, including basic and acidic fibroblast growth factor, interleukin-6, platelet-derived growth factor, and transforming growth factor-beta. By contrast, CD19 overexpression enhanced wound healing and cytokine expression. Hyaluronan (HA), an endogenous ligand for toll-like receptor (TLR)-4, stimulated B cells, which infiltrates into wounds to produce interleukin-6 and transforming growth factor-beta through TLR4 in a CD19-dependent manner. CD19 expression regulated TLR4 signaling through p38 activation. HA accumulation was increased in injured skin tissue relative to normal skin, and exogenous application of HA promoted wound repair in wild-type but not CD19-deficient mice, suggesting that the beneficial effects of HA to the wound-healing process are CD19-dependent. Collectively, these results suggest that increased HA accumulation in injured skin induces cytokine production by stimulating B cells through TLR4 in a CD19-dependent manner. Thus, this study is the first to reveal a critical role of B cells and novel mechanisms in wound healing.
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PMID:CD19, a response regulator of B lymphocytes, regulates wound healing through hyaluronan-induced TLR4 signaling. 1957 28

Paraquat (PQ) can cause acute lung injury in humans and experimental animals. However, the role of growth factors in the progression of injury has not been clearly established. We developed an animal model of PQ-induced lung injury using Wistar rats. One milliliter of PQ solution (30, 60, and 120 mg/kg) was applied through the lavage, while the same amount of vehicle was applied to control rats. Based on histopathology, the lungs of some animals exposed to PQ showed acute fulmination, resulting in death, while others showed a more protracted injury, resulting in typical pulmonary fibrosis at 21 days. Using this PQ-poisoned rat model, we examined the intrapulmonary gene expression and circulatory level of cytokines and growth factors at 8 hours, 24 hours, 3 days, 7 days, 14 days, and 21 days after PQ administration. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the gene expression levels of interleukin-1 beta and interleukin-6 were significantly increased at 21 days after PQ challenge compared with the controls. The mRNA expression of tumor necrosis factor-alpha was also significantly increased except on days 14 and 21 after PQ treatment. Moreover, PQ-treated rats showed enhanced gene expression of growth factors such as platelet-derived growth factor-A and insulin-like growth factor-1 at 21 days and transforming growth factor-beta 1 at 14 days. ELISA results showed the circulatory level of cytokines and growth factors coincided with intrapulmonary gene expression. The synergistic effects of these molecules are presumed to cause pulmonary damage due to PQ challenge and may become targets of treatment.
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PMID:Role of growth factors in acute lung injury induced by paraquat in a rat model. 2049 31


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