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Journal of the American Society of Nephrology 03/2013; · 9.66 Impact Factor
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ABSTRACT: Conjugated linoleic acid (CLA) induces regression of preestablished atherosclerosis in the ApoE(-/-) mouse. Understanding the mechanisms involved may help in identifying novel pathways associated with the regression of human disease. Animals were administered a 1% cholesterol diet for 12 wk, with 1% CLA supplementation from wk 8 to 12. ApoE(-/-) mice fed only the 1% cholesterol diet for 12 wk were employed as controls. Transcriptomic analysis of mouse aorta showed that many of the components of the IL-10 signaling pathway were modified during CLA-induced regression. Real-time PCR and Western blot analysis showed increased IL-10 receptor expression, phosphorylation of STAT3, and downstream target gene expression in the aorta, alongside an increase in serum IL-10 (79.8±22.4 vs. 41.9±5.5 pg/ml, n=10; P<0.01). CLA -supplementation also increased IL-10 production in bone marrow-derived macrophages (143.6±28.6 vs. 94±5.6 pg/ml, n=5; P<0.05). To explore the mechanisms for altered IL-10 production, we examined the profile of monocyte/macrophage phenotype in the vessel wall, bone marrow, and spleen. CLA increased macrophage polarization toward an anti-inflammatory M2 phenotype in vivo, increasing the population of Ly6C(lo) monocytes (29 vs. 77±14, n=5, P < 0.05) in the aorta. CLA had similar effects on monocytes/macrophages differentiated from marrow-derived progenitor cells and on splenocytes. The induction of IL-10 on CLA supplementation in this model may reflect a systemic alteration toward an anti-inflammatory phenotype, which, in turn promotes increased vascular infiltration by Ly6C(lo) monocytes. These cells may contribute to CLA-induced disease regression.-McCarthy, C., Duffy, M. M., Mooney, D., James, W. G., Griffin, M. D., Fitzgerald, D. J., Belton, O. IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis.
The FASEB Journal 10/2012; · 5.71 Impact Factor
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ABSTRACT: BACKGROUND: After the first year after kidney transplantation, 3% to 5% of grafts fail each year but detailed studies of how grafts progress to failure are lacking. This study aimed to analyze the functional stability of kidney transplants between 1 and 5 years after transplantation and to identify initially well-functioning grafts with progressive decline in allograft function. METHODS: The study included 788 adult conventional kidney transplants performed at the Mayo Clinic Rochester between January 2000 and December 2005 with a minimum graft survival and follow-up of 2.6 years. The modification of diet in renal disease equation for estimating glomerular filtration rate (eGFRMDRD) was used to calculate the slope of renal function over time using all available serum creatinine values between 1 and 5 years after transplantation. RESULTS: Most transplants demonstrated good function (eGFRMDRD ≥40 mL/min) at 1 year with positive eGFRMDRD slope between 1 and 5 years after transplantation. However, a subset of grafts with 1-year eGFRMDRD ≥40 mL/min exhibited strongly negative eGFRMDRD slope between 1 and 5 years suggestive of progressive loss of graft function. Forty-one percent of this subset reached graft failure during follow-up, accounting for 69% of allograft failures occurring after 2.5 years after transplantation. This pattern of progressive decline in estimated glomerular filtration rate despite good early function was associated with but not fully attributable to factors suggestive of enhanced antidonor immunity. CONCLUSIONS: Longitudinal analysis of serial estimated glomerular filtration ratemeasurements identifies initially well-functioning kidney transplants at high risk for subsequent graft loss. For this subset, further studies are needed to identify modifiable causes of functional decline.
Transplantation 10/2012; · 4.00 Impact Factor
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Matthew D Griffin
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ABSTRACT: Mononuclear phagocytes (macrophages, dendritic cells, and monocytes) play a complex role in kidney disease. Techniques for selectively depleting them in rodents have made important contributions but have also generated some contradictory results. Ferenbach et al. report that two widely used mononuclear phagocyte depletion techniques differentially affect early severity of renal ischemia/reperfusion injury and provide evidence that this may be due to a residual, protective subset that persists in the kidney after one of the two techniques.
Kidney International 10/2012; 82(8):835-7. · 6.61 Impact Factor
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ABSTRACT: Interleukin 17A-secreting T-helper 17 (Th17) cells are pathogenic in inflammatory kidney diseases, but their intrarenal regulation is poorly understood. In order to better define Th17 cell dynamics during interstitial inflammation, we utilized the mouse unilateral ureteral obstruction model to analyze inflammatory cell subtypes by multicolor flow cytometry and cell sorting and by effects on in vitro-generated Th17 cells. Interleukin 17A expression localized to CCR6(+)CCR4(+/-)CD4(+) T-cells and progressively increased in obstructed kidneys. The number of CCR6(+)CD4(+) T-cells increased over 10-fold by 72 h, were enriched for interleukin 17A production, and were highly proliferative based on in vivo bromodeoxyuridine incorporation. Secreted products of leukocytes isolated from obstructed kidneys enhanced the interleukin 17A production of in vitro-generated Th17 cells. This Th17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking the interleulin-1 receptor and in mice treated with a recombinant interleukin-1 receptor antagonist, each of which exhibited reduced intrarenal Th17 activity compared with control mice. Thus, the inflamed kidney accumulates CCR6(+) Th17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intrarenal Th17 activation in acute kidney injury.
Kidney International 02/2012; 81(4):379-90. · 6.61 Impact Factor
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ABSTRACT: Circulating neutrophils are essential for innate immunity and undergo rapid, stepwise adhesion to and transmigration through the endothelium following tissue injury and microbial invasion. Neutrophil dysfunction may contribute to morbidity and mortality in acute kidney injury but has not frequently been studied at a mechanistic level. Rossaint et al. provide experimental evidence in mice and humans that acute uremia causes discrete intracellular signaling abnormalities that interfere with specific stages of neutrophil trafficking during inflammation.
Kidney International 09/2011; 80(5):447-50. · 6.61 Impact Factor
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Michelle M. Duffy,
Jana Pindjakova,
Shirley A. Hanley,
Cathal McCarthy,
Gudrun A. Weidhofer,
Eva M. Sweeney,
Karen English,
Georgina Shaw,
J. Mary Murphy,
Frank P. Barry,
Bernard P. Mahon,
Orina Belton,
Rhodri Ceredig, Matthew D. Griffin
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ABSTRACT: Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4+ T cells toward the Th17 phenotype was examined. CD4+ T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell–cell contact was prevented. Th17 cultures from highly purified naïve- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.
European Journal of Immunology 08/2011; 41(10):2840 - 2851. · 5.10 Impact Factor
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ABSTRACT: Mesenchymal stem (stromal) cells (MSCs) are rare, multipotent progenitor cells that can be isolated and expanded from bone marrow and other tissues. Strikingly, MSCs modulate the functions of immune cells, including T cells, B cells, natural killer cells, monocyte/macrophages, dendritic cells, and neutrophils. T cells, activated to perform a range of different effector functions, are the primary mediators of many autoimmune and inflammatory diseases as well as of transplant rejection and graft-versus-host disease. Well-defined T-cell effector phenotypes include the CD4+ (T helper cell) subsets Th1, Th2, and Th17 cells and cytotoxic T lymphocytes derived from antigen-specific activation of naïve CD8+ precursors. In addition, naturally occurring and induced regulatory T cells (Treg) represent CD4+ and CD8+ T-cell phenotypes that potently suppress effector T cells to prevent autoimmunity, maintain self-tolerance, and limit inflammatory tissue injury. Many immune-mediated diseases entail an imbalance between Treg and effector T cells of one or more phenotypes. MSCs broadly suppress T-cell activation and proliferation in vitro via a plethora of soluble and cell contact-dependent mediators. These mediators may act directly upon T cells or indirectly via modulation of antigen-presenting cells and other accessory cells. MSC administration has also been shown to be variably associated with beneficial effects in autoimmune and transplant models as well as in several human clinical trials. In a small number of studies, however, MSC administration has been found to aggravate T cell-mediated tissue injury. The multiple effects of MSCs on cellular immunity may reflect their diverse influences on the different T-cell effector subpopulations and their capacity to specifically protect or induce Treg populations. In this review, we focus on findings from the recent literature in which specific modulatory effects of MSCs on one or more individual effector T-cell subsets and Treg phenotypes have been examined in vitro, in relevant animal models of in vivo immunological disease, and in human subjects. We conclude that MSCs have the potential to directly or indirectly inhibit disease-associated Th1, Th2, and Th17 cells as well as cytotoxic T lymphocytes but that many key questions regarding the potency, specificity, mechanistic basis, and predictable therapeutic value of these modulatory effects remain unanswered.
Stem Cell Research & Therapy 08/2011; 2(4):34. · 3.21 Impact Factor
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ABSTRACT: Allogeneic mesenchymal stem or stromal cells (MSCs) are proposed as cell therapies for degenerative, inflammatory, and autoimmune diseases. The feasibility of allogeneic MSC therapies rests heavily on the concept that these cells avoid or actively suppress the immunological responses that cause rejection of most allogeneic cells and tissues. In this article the validity of the immune privileged status of allogeneic MSCs is explored in the context of recent literature. Current data that provide the mechanistic basis for immune modulation by MSCs are reviewed with particular attention to how MSCs modify the triggering and effector functions of innate and adaptive immunity. The ability of MSCs to induce regulatory dendritic and T-cell populations is discussed with regard to cell therapy for autoimmune disease. Finally, we examine the evidence for and against the immune privileged status of allogeneic MSCs in vivo. Allogeneic MSCs emerge as cells that are responsive to local signals and exert wide-ranging, predominantly suppressive, effects on innate and adaptive immunity. Nonetheless, these cells also retain a degree of immunogenicity in some circumstances that may limit MSC longevity and attenuate their beneficial effects. Ultimately successful allogeneic cell therapies will rely on an improved understanding of the parameters of MSC-immune system interactions in vivo.
Human gene therapy 12/2010; 21(12):1641-55. · 4.20 Impact Factor
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ABSTRACT: Lack of knowledge regarding specific causes for late loss of kidney transplants hampers improvements in long-term allograft survival. Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival. This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low-risk cohort and characterized the nature of the inflammation. We studied 151 living-donor, tacrolimus/mycophenolate-treated recipients without overt risk factors for reduced graft survival. Transplants with normal histology (n = 86) or fibrosis alone (n = 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n = 20) exhibited a decline in GFR and reduced graft survival. Immunohistochemistry confirmed increased interstitial T cells and macrophages/dendritic cells in the group with both fibrosis and inflammation, and there was increased expression of transcripts related to innate and cognate immunity. Pathway- and pathologic process-specific analyses of microarray profiles revealed that potentially damaging immunologic activities were enriched among the overexpressed transcripts (e.g., Toll-like receptor signaling, antigen presentation/dendritic cell maturation, IFN-γ-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes). Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes. Early interventions aimed at altering rejection-like inflammation may improve long-term survival of kidney allografts.
Journal of the American Society of Nephrology 11/2010; 21(11):1987-97. · 9.66 Impact Factor
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ABSTRACT: The genetic modification of organs or cells is an attractive approach to protect allogeneic transplants from acute rejection and other complications. The transplant setting offers a unique opportunity to utilize ex vivo gene therapy for the modification of allogeneic organs and tissues prior to implantation. However, significant challenges exist in the application of this concept to human organ transplantation, including the large number of potential molecular targets, the diversity and safety profile of available vector delivery systems and the merging of gene-based therapies with existing immunosuppressive regimens. Accordingly, many different therapeutic concepts and vector systems have been investigated in preclinical studies with the aim of prolonging allograft survival. However, the translation of promising gene therapy strategies to transplant clinical trials has lagged behind the progress made in other medical fields. This review describes the recent preclinical applications of gene transfer to transplantation, and critically evaluates the degree to which gene therapy has been tested clinically in organ transplant recipients.
Current opinion in molecular therapeutics 10/2009; 11(5):504-12. · 3.68 Impact Factor
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Latonya J Hickson,
Manish Gera,
Hatem Amer,
Corey W Iqbal,
Therese B Moore,
Dawn S Milliner,
Fernando G Cosio,
Timothy S Larson,
Mark D Stegall,
Michael B Ishitani,
James M Gloor, Matthew D Griffin
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ABSTRACT: For a subset of adults and children with primary focal segmental glomerulosclerosis (FSGS), proteinuria and renal dysfunction recur after kidney transplantation (KTx). Predicting recurrence and response to plasmapheresis (PP) or other interventions remains problematic.
The prevalence, recurrence rate, outcomes, and treatment responses of patients with FSGS were determined among 1573 KTx recipients. Although 5.0% carried some diagnosis of FSGS, only 1.9% (n=30) met strict diagnostic criteria for primary FSGS including biopsy-proven FSGS, lack of secondary factors, negative family history, and progression to end-stage renal disease within 10 years.
Of these, 47% had recurrent FSGS compared with 8% of those not meeting strict criteria (P<0.001). Recurrence was more common in children compared with adults (86% vs. 35%, P=0.01). Graft survival was lower for recipients with primary FSGS compared with all others and inferior graft survival was attributable to recurrent FSGS. Fourteen patients received PP preemptively (pre-KTx) or therapeutically (post-KTx) for recurrent disease. Four pediatric patients additionally received anti-CD20 (rituximab) therapy. Of the different treatment approaches, only PP combined with rituximab was associated with prolonged remission of proteinuria.
The results indicate that patients at high risk for FSGS recurrence can be identified and may benefit from carefully planned peritransplant interventions.
Transplantation 05/2009; 87(8):1232-9. · 4.00 Impact Factor
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ABSTRACT: Interstitial monocytic infiltration of the kidney occurs within hours of acute kidney injury and is an important determinant of functional decline and fibrosis. Li et al. used several surface markers to distinguish between dendritic cells and inflammatory monocytes following acute kidney injury and to identify two chemokine receptors that regulate monocyte traffic. This Commentary examines the degree to which monocyte-lineage diversity, trafficking, and contribution to renal injury have been teased out to date.
Kidney International 01/2009; 74(12):1509-11. · 6.61 Impact Factor
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ABSTRACT: Pulmonary hypertension (PH) is common in patients on dialysis where it is associated with reduced survival. The possible association between PH and kidney transplant recipient survival has not been previously evaluated.
In this retrospective study, we screened for PH pretransplant in 215 transplant candidates using cardiac echocardiography and measurements of right ventricular systolic pressure (RVSP).
Sixty-eight percent of patients had normal RVSP (<35 mm Hg), 47 (22%) had mild to moderately elevated RVSP (36-50), and 22 (10%) had markedly elevated RVSP more than 50 suggestive of severe PH. Time on dialysis was the strongest correlate of an elevated RVSP (r=0.253, P<0.001) and this relationship was independent of other variables. Elevated RVSP was observed in 25%, 25%, 38%, and 58% of patients not on dialysis, on dialysis for less than 1 year, more than 1 to 2 years, or more than 2 years, respectively. An RVSP more than 50 was associated with significantly reduced posttransplant survival (hazard ratio =3.75 [1.17-11.97], P=0.016). This relationship seemed to be independent of other variables including older age, reduced left ventricular ejection fraction, low serum albumin, and delayed graft function.
These analyses suggest for the first time that pretransplant PH correlates with patient survival after kidney transplantation.
Transplantation 12/2008; 86(10):1384-8. · 4.00 Impact Factor
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ABSTRACT: Acute urinary obstruction causes interstitial inflammation with leukocyte accumulation and the secretion of soluble mediators. Here we show that unilateral ureteral ligation caused a progressive increase in renal F4/80(+) and F4/80(-) dendritic cells, monocytes, neutrophils and T-cells 24-72 h following obstruction. Depletion of dendritic cells by clodronate pretreatment showed these cells to be the most potent source of tumor necrosis factor and other pro-inflammatory mediators in the obstructed kidney. F4/80(+) dendritic cells and T-cells co-localized in the cortico-medullary junction and cortex of the obstructed kidney. Cytokine secretion patterns and surface phenotypes of T-cells from obstructed kidneys were found to include interferon-gamma-secreting CD4(+) and CD8(+) memory T-cells as well as interleukin 17 (IL-17)-secreting CD4(+) memory T-cells. Depletion of the intra-renal dendritic cells prior to ligation did not numerically reduce T-cells in obstructed kidneys but attenuated interferon-gamma and IL-17-competent T-cells. Our study shows that intra-renal dendritic cells are a previously unidentified early source of proinflammatory mediators after acute urinary obstruction and play a specific role in recruitment and activation of effector-memory T-cells including IL-17-secreting CD4(+) T-cells.
Kidney International 12/2008; 74(10):1294-309. · 6.61 Impact Factor
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ABSTRACT: Clinicians and other health care professionals involved in the evaluation and management of organ transplant recipients and organ donors quite commonly encounter ethically complex scenarios during the course of their work. The response to such challenging situations may be influenced by personal experiences and beliefs, programmatic or institutional policy, existing legislation, published literature, and consultative analysis by experts in the field of biomedical ethics. As organ transplantation continues to evolve in its scope, complexity, and global reach, there is a growing need for transplant programs to carefully discuss and reach consensus on how to deal with specific ethical issues that may arise. In this article, we present the summaries of 3 clinically relevant case scenarios from the 2007 Mayo Clinic Course in Transplant Ethics, along with the results of audience responses and discussion facilitated by a volunteer panel of experts from North America. The cases provide cogent examples of how open, consensus-driven discussion of specific ethically charged scenarios can be useful in guiding progressive clinical practices in organ transplantation.
Transplantation reviews (Orlando, Fla.) 07/2008; 22(3):178-83.
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ABSTRACT: Analysis of 1-year surveillance biopsies was carried out for kidney transplant recipients participating in a randomized trial comparing tacrolimus- and sirolimus-based immunosuppression. The analysis was restricted to recipients remaining on assigned regimen throughout the first posttransplant year. Biopsies from 57 of 84 (68%) tacrolimus-randomized recipients were compared with 38 of 81 (47%) of sirolimus-randomized recipients, the discrepancy being explained by a higher rate of sirolimus discontinuation for non-graft-related complications. Included recipients from the two groups did not differ for baseline characteristics or 1-year iothalamate clearance. Histologic analysis indicated no differences between the groups for glomerular, arterial/arteriolar, or acute interstitial abnormalities. There were, however, significantly higher mean scores in the tacrolimus group for interstitial fibrosis and tubular atrophy with a trend toward higher estimated percent interstitial fibrosis. The results indicate that sirolimus may be associated with reduced early graft fibrosis compared with tacrolimus. This potential benefit is offset by lower success rate in maintaining the regimen and was not accompanied by superior glomerular filtration rate at 1 year.
Transplantation 05/2008; 85(8):1212-5. · 4.00 Impact Factor
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ABSTRACT: Polyomavirus-associated nephropathy (PVAN) is a significant cause of allograft loss after renal transplantation. A noninvasive assay that can guide the evaluation of PVAN would be of clinical value. We compared the utility of BK virus (BKV) polymerase chain reaction (PCR) and urine cytology in screening for concurrent PVAN.
We used PCR to test urine and plasma samples from renal recipients simultaneously for BKV DNA. Additionally, we tested urine samples for decoy cells. Sample results were correlated with biopsy-proven PVAN. Receiver-operator characteristic curves were used to determine viral load thresholds associated with concurrent PVAN.
In this cross-sectional study, BKV viruria, viremia, and urinary decoy cells were detected in 24%, 9%, and 13% of renal recipients, respectively. Among 114 patients who had renal allograft biopsy, four (3.5%) were diagnosed with PVAN. Using pathology as gold standard for the diagnosis of PVAN, BKV viremia threshold of >1.6E+04 copies/mL had 100% sensitivity, 96% specificity, 50% positive predictive value, and 100% negative predictive value. A BKV viruria threshold of >2.5E+07 copies/mL had 100% sensitivity, 92% specificity, 31% positive predictive value, and 100% negative predictive value. In contrast, urine decoy cells had 25% sensitivity, 84% specificity, 5% positive predictive value, and 97% negative predictive value for the diagnosis of concurrent PVAN.
BKV PCR may be a clinically useful noninvasive test to identify renal recipients with concurrent PVAN. BKV DNA >1.6E+04 copies/mL of plasma and >2.5E+07 copies/mL of urine were highly associated with concurrent PVAN whereas a negative PCR test makes the diagnosis of PVAN highly unlikely.
Transplantation 08/2007; 84(3):340-5. · 4.00 Impact Factor
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Michal J Tracz,
Julio P Juncos,
Joseph P Grande,
Anthony J Croatt,
Allan W Ackerman,
Govindarajan Rajagopalan,
Keith L Knutson,
Andrew D Badley, Matthew D Griffin,
Jawed Alam,
Karl A Nath
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ABSTRACT: Lipopolysaccharide (LPS) induces the stress-responsive gene heme oxygenase-1 (HO-1). The present study examined the significance of HO-1 in response to LPS. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked a greater reduction in glomerular filtration rate and renal blood flow, increased renal cytokine expression, and increased activation of nuclear factor (NF)-kappaB. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-kappaB and less phosphorylation of its inhibitor, IkappaB. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked markedly greater elevations in serum levels of Th1 cytokines, Th2 cytokines, chemokines, and cytokines that stimulate bone marrow progenitors. The liver, a major source of serum cytokines, showed an increased activation of NF-kappaB in LPS-treated HO-1(-/-) mice. In addition, LPS provoked widespread apoptosis of immune cells in the spleen and thymus in HO-1(-/-) mice but not in HO-1(+/+) mice. We conclude that HO-1 deficiency exhibits a heightened and dysregulated inflammatory response to LPS accompanied by greater impairment in renal hemodynamic response and widespread apoptosis of immune cells. Because polymorphisms in the HO-1 gene with diminished HO activity predispose to human disease, we speculate that our findings may be relevant to the clinical outcome in patients with sepsis syndromes.
American Journal Of Pathology 07/2007; 170(6):1820-30. · 4.89 Impact Factor
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ABSTRACT: The immunological effects of vitamin D receptor (VDR) ligands include inhibition of dendritic cell (DC) maturation, suppression of T-helper type 1 (Th1) T-cell responses and facilitation of antigen-specific immune tolerance in vivo. While studying the molecular profile of DCs cultured in the presence of 1alpha,25(OH)D3 or synthetic D3 analogs we observed that expression of the NF-kappaB family member RelB, which plays an essential role in DC differentiation and maturation, is selectively suppressed by VDR ligands. Further in vitro and in vivo studies of VDR-mediated RelB suppression indicated that the mechanism for this effect involves direct binding of VDR/RXR alpha to a defined region of the relB promoter and assembly of a negative regulatory complex containing HDAC3, HDAC1, SMRT and, most likely, other factors. Interestingly, promoter engagement by VDR and HDAC3, but not the other identified components, is enhanced by addition of a VDR ligand and inhibited by a pro-maturational stimulus (LPS) that results in RelB upregulation. Promoter assays in a panel of cell lines suggest that the VDR ligand-dependent component of relB suppression may occur selectively in antigen presenting cells. Cell type-specific, ligand-enhanced negative transcriptional regulation represents a potentially novel paradigm for VDR-controlled genes. In this report we review the experimental data to support such a mechanism for relB regulation in DCs and present a model for the process.
Archives of Biochemistry and Biophysics 05/2007; 460(2):218-26. · 2.93 Impact Factor
