396 research outputs found
EGF and hypoxia-induced expression of CXCR4 on non-small cell lung cancer cells is regulated by the PI3-kinase/PTEN/AKT/mTOR signaling pathway and activation of HIF-1alpha
No full textNovel CXCR2â dependent liver regenerative qualities of ELRâ containing CXC chemokines
No full textSevere acute liver injury due to accidental or intentional acetaminophen overdose presents a major clinical dilemma often requiring liver transplantation. In the present study, liver regeneration after profound liver injury in mice challenged with acetaminophen was facilitated by the exogenous addition of ELRâ containing CXC chemokines such as macrophage inflammatory proteinâ 2 (MIPâ 2), epithelial neutrophilâ activating proteinâ 78 (ENAâ 78), or interleukin 8. Intravenous administration of ELRâ CXC chemokines or Nâ acetylâ cysteine (NAC) immediately after acetaminophen challenge in mice significantly reduced histological and biochemical markers of hepatic injury. However, when the intervention was delayed until 10 h after acetaminophen challenge, only ELRâ CXC chemokines significantly reduced liver injury and mouse mortality. The delayed addition of ELRâ CXC chemokines to cultured hepatocytes maintained the proliferation of these cells in a CXCR2â dependent fashion after acetaminophen challenge whereas delayed NAC treatment did not. These observations demonstrate that ELRâ CXC chemokines represent novel hepatic regenerative factors that exhibit prolonged therapeutic effects after acetaminophenâ induced hepatotoxicity.â Hogaboam, C. M., Boneâ Larson, C. L., Steinhauser, M. L., Lukacs, N. W., Colletti, L. M., Simpson, K. J., Strieter, R. M., Kunkel, S. L. Novel CXCR2â dependent liver regenerative qualities of ELRâ containing CXC chemokines. FASEB J. 13, 1565â 1574 (1999)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154508/1/fsb2fasebj13121565.pd
Recombinant Human Adenovirus with Rat MIP-2 Gene Insertion Causes Prolonged PMN Recruitment to the Murine Brain
No full textSingle injections of recombinant cytokines/chemokines into tissue have provided insights into their possible roles during the inflammatory response. Adenoviral technology may allow us to mimic the in vivo situation more closely, with protein generated in a continuous but transient fashion. Replication-deficient human type 5 adenovirus containing a rat macrophage inflammatory protein-2 ( MIP-2 ) gene insertion and cytomegalovirus promoter was injected into the mouse brain to investigate the inflammatory response to continuous overproduction of MIP-2. Adenovirus with a LacZ gene insertion expressing Β-galactosidase was used as a control. At doses of 10 4 to 10 7 plaque-forming units, a minimal inflammatory response was detected to the LacZ virus, with leukocyte recruitment that was restricted to the injection site. A dose of 10 7 plaque-forming units of both the LacZ and the MIP-2 vector produced extensive transgene product expression that persisted for at least 7 days. Astrocytes, recognized by their morphology, were the predominant cell type expressing MIP-2 and Β-galactosidase. A dose of 10 7 plaque-forming units of MIP-2 vector caused dramatic polymorphonuclear leukocyte (PMN) recruitment to the brain parenchyma after 2 days. PMN recruitment was still observed after 4 and 7 days, but had become more localized to the injection site and was associated with numerous foam-like macrophages. At both 2 and 7 days the blood-brain barrier was breached in the region of leukocyte recruitment. Despite the extent of leukocyte recruitment there were no overt signs of neuronal degeneration or demyelination. Our findings demonstrate that continuous production of MIP-2 in the CNS results in persistent PMN recruitment to the brain parenchyma with no evidence of tachyphylaxis. The lack of PMN recruitment to the brain parenchyma following CNS injury may be a result of deficient production of PMN chemoattractants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75633/1/j.1460-9568.1996.tb01324.x.pd
Endogenous modulators of TNF and IL-1 response are under partial control of TNF in baboon bacteremia
No full textEndogenous modulators of TNF and IL-1 response are under partial control of TNF in baboon bacteremia. Redl H, Schlag G, Paul E, Bahrami S, Buurman WA, Strieter RM, Kunkel SL, Davies J, Foulkes R. Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria. Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines for which naturally occurring inhibitors have been identified. The present study was undertaken to evaluate the extent to which scavenging of TNF in bacteremia attenuates the plasma levels of IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors (sTNFR). Ten male baboons received 2 x 10(9) colony-forming units/kg live Escherichia coli over 2 h and were subjected to either placebo or anti-TNF antibody (anti-TNF Ab) treatment (1 mg/kg CDP571, Celltech, UK) 2 h before E. coli infusion (observation time: 72h). IL-1ra (range: 50-100 ng/ml) and sTNFR (range: 55kDa, 20-25 ng/ml; 75 kDa, 30-35 ng/ml) release was more sustained than that of IL-1 and TNF and was significantly attenuated by anti-TNF treatment, as were the circulating levels of IL-1, IL-8, and monocyte chemotactic peptide-1 (MCP-1) in the anti-TNF Ab group. We conclude that the increase in circulating natural cytokine modulators observed in nonhuman primate bacteremia is under the partial control of endogenous TNF because it was influenced by anti-TNF pretreatment. This attenuation is comparable to the anti-TNF effect on the chemokine MCP-1
Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3.
No full textWe investigated possible cellular receptors for the human CXC chemokine platelet factor-4 variant/CXCL4L1, a potent inhibitor of angiogenesis. We found that CXCL4L1 has lower affinity for heparin and chondroitin sulfate-E than platelet factor-4 (CXCL4) and showed that CXCL10 and CXCL4L1 could displace each other on microvascular endothelial cells. Labeled CXCL4L1 also bound to CXCR3A- and CXCR3B-transfectants and was displaced by CXCL4L1, CXCL4, and CXCL10. The CXCL4L1 anti-angiogenic activity was blocked by anti-CXCR3 antibodies (Abs) in the Matrigel and cornea micropocket assays. CXCL4L1 application in CXCR3(-/-) or in wild-type mice treated with neutralizing anti-CXCR3 Abs, resulted in reduced inhibitory activity of CXCL4L1 on tumor growth and vascularization of Lewis lung carcinoma. Furthermore, CXCL4L1 and CXCL4 chemoattracted activated T cells, human natural killer cells, and human immature dendritic cells (DCs). Migration of DCs toward CXCL4 and CXCL4L1 was desensitized by preincubation with CXCL10 and CXCL11, inhibited by pertussis toxin, and neutralized by anti-CXCR3 Abs. Chemotaxis of T cells, natural killer cells, and DCs is likely to contribute to the antitumoral action. However, the in vivo data indicate that the angiostatic property of CXCL4L1 is equally important in retarding tumor growth. Thus, both CXCR3A and CXCR3B are implicated in the chemotactic and vascular effects of CXCL4L1.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe
Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer
No full textMinu K Srivastava,1,2 Li Zhu,1,2 Marni Harris-White,2 Min Huang,1–3 Maie St John,1,3 Jay M Lee,1,3 Ravi Salgia,4 Robert B Cameron,1,3,5 Robert Strieter,6 Steven Dubinett,1–3 Sherven Sharma1–31Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 3Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Department of Medicine, University of Chicago, Chicago, IL, 5Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 6Department of Medicine, University of Virginia, Charlottesville, VA, USAAbstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with immunotherapies. Optimization of combined approaches that simultaneously downregulate MDSC suppressor pathways, restore APC immune-stimulating activity, and expand tumor-reactive T cells will be useful in improving therapy.Keywords: MDSCs, antigen-presenting cells, natural killer cell activation, T-cell activation, immunotherap
CCL2 responses to Mycobacterium tuberculosis are associated with disease severity in tuberculosis.
No full textBACKGROUND Leucocyte activating chemokines such as CCL2, CCL3, and CXCL8 together with proinflammatory IFNgamma, TNFalpha and downmodulatory IL10 play a central role in the restriction of M. tuberculosis infections, but is unclear whether these markers are indicative of tuberculosis disease severity. METHODOLOGY We investigated live M. tuberculosis- and M. bovis BCG-induced peripheral blood mononuclear cell responses in patients with tuberculosis (TB) and healthy endemic controls (ECs, n = 36). TB patients comprised pulmonary (PTB, n = 34) and extrapulmonary groups, subdivided into those with less severe localized extrapulmonary TB (L-ETB, n = 16) or severe disseminated ETB (D-ETB, n = 16). Secretion of CCL2, IFNgamma, IL10 and CCL3, and mRNA expression of CCL2, TNFalpha, CCL3 and CXCL8 were determined. RESULTS M. tuberculosis- and BCG-induced CCL2 secretion was significantly increased in both PTB and D-ETB (p<0.05, p<0.01) as compared with L-ETB patients. CCL2 secretion in response to M. tuberculosis was significantly greater than to BCG in the PTB and D-ETB groups. M. tuberculosis-induced CCL2 mRNA transcription was greater in PTB than L-ETB (p = 0.023), while CCL2 was reduced in L-ETB as compared with D-ETB (p = 0.005) patients. M. tuberculosis-induced IFNgamma was greater in L-ETB than PTB (p = 0.04), while BCG-induced IFNgamma was greater in L-ETB as compared with D-ETB patients (p = 0.036). TNFalpha mRNA expression was raised in PTB as compared with L-ETB group in response to M. tuberculosis (p = 0.02) and BCG (p = 0.03). Mycobacterium-induced CCL3 and CXCL8 was comparable between TB groups. CONCLUSIONS The increased CCL2 and TNFalpha in PTB patients may support effective leucocyte recruitment and M. tuberculosis localization. CCL2 alone is associated with severity of TB, possibly due to increased systemic inflammation found in severe disseminated TB or due to increased monocyte infiltration to lung parenchyma in pulmonary disease
A mathematical model of the rabbit cortical collecting tubule
No full text The epithelium of the cortical collecting tubule of the rabbit is represented as four well-stirred compliant compartments corresponding to principal cell, alpha- and beta-intercalated cells, and lateral interspace. Model variables include the concentrations of Na, K, Cl, and HCO3, pH, cell volume, and electrical potential. The model equations specify mass conservation and chemical equilibrium for buffer reactions. Ionic conductance is represented by the Goldman constant-field equation. For the intercalated cells, phenomenological expressions describing the proton pumps are structured to agree with data of O. S. Andersen, J. E. N. Silveira, and P. R. Steinmetz (J. Gen. Physiol. 86: 215-234, 1985) in the turtle bladder. Coupled transport via Na/H and Cl/HCO3 exchangers is represented according to the formalism of linear nonequilibrium thermodynamics. To construct the tubule model, the flat epithelium is wrapped into a cylinder, creating a luminal compartment. Luminal variables include volume flow, hydrostatic pressure, electrical potential, and ionic concentrations. A specific aim of this investigation was to simulate the capability of the epithelium to maintain Na reabsorption in the presence of low luminal salt concentration. In this regard, critical features of the model include tight junctional conductance and the apical Na permeability of the principal cell. In particular, we examine a principal cell apical Na permeability inversely dependent on luminal and intracellular Na concentrations (M. M. Civan and R. J. Bookman. J. Membr. Biol. 65: 63-80, 1982). This concentration-dependent permeability together with a low junctional conductance produces three results congruent with experimental data: 1) dilution of luminal Na and maintenance of reabsorptive Na transport despite a steep transtubular gradient, 2) a relatively constant level of K secretion over a wide range of luminal Na concentrations, and 3) a relatively constant transepithelial potential over this range of luminal Na. </jats:p
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BIOCHEMICAL STUDIES OF FABRY DISEASE AND FUCOSIDOSIS
No full textLysosomal storage diseases affect about 1 in 5000 live births but most of them remain without treatment options. Fabry disease is commonly treated with enzyme replacement therapy, but kidney pathology remains problematic. We have engineered a smaller form of the treatment enzyme that should increase the concentration of protein that is able to reach a key part of the kidney filtration barrier, the podocytes. Our enzyme retains the ability to cleave Gb3, retains activity better than wild type in conditions relevant to enzyme replacement therapy and remains 99% identical to the wild type protein sequence. For another glycosidase deficiency, fucosidosis, we have established an expression system for the glycosylated form of alpha-L-fucosidase and demonstrate the potential of deoxyfuconojirimycin (DFJ) and fucose as pharmacological chaperones. Both chaperones were able to increase the lysosomal colocalization of the disease mutant S155F and both greatly stabilize the wild type enzyme at both acidic and neutral pH. These studies provide initial insights into two important treatment options for fucosidosis and warrant deeper investigations of both in cellular and animal models of the disease.Molecular and Cellular BiologyDoctor of Philosophy (Ph.D.
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