Biomedical subjects

R W Johnson

Publications and source records attributed to R W Johnson.

At least 19 recordsLinked to original sources

PubMed2006

Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120.

The number of older adults with HIV-1 disease is increasing but little is known about how age influences behavioral deficits associated with HIV-1 infection. The purpose of this study was to determine in a murine model if aging influenced sickness behavior following central injection of HIV-1 gp120. In initial studies, behavioral deficits induced by acute and repeated intracerebroventricular (ICV) injection of gp120 were greater in aged mice than in adults. Furthermore, repeated ICV injection of gp120 increased hippocampal levels of IL-1 beta and IL-6 mRNA in aged mice but not in adults. To determine if IL-6, which is elevated in aged brain, affects expression of the gp120-binding target, CCR5, microglia (BV-2 cell line) were incubated with increasing concentrations of IL-6. Cell surface expression of CCR5 was increased by IL-6 in a dose-dependent manner. Additionally, IL-6 increased gp120-dependent chemotaxis. These results suggest that aging increases the sensitivity of mice to behavioral deficits caused by ICV gp120, perhaps by increasing expression of CCR5 and augmenting production of cytokines.

Aging↗

PubMed2006

Variants in Apaf-1 segregating with major depression promote apoptosome function.

APAF1, encoding the protein apoptosis protease activating factor 1 (Apaf-1), has recently been established as a chromosome 12 gene conferring predisposition to major depression in humans. The molecular phenotypes of Apaf-1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf-1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell. Cellular phenotypes were measured using a yeast heterologous expression assay in which human Apaf-1 and other proteins necessary to constitute a functional apoptotic pathway were overexpressed. Apaf-1 variants encoded by APAF1 alleles that segregate with major depression in families linked to chromosome 12 shared a common gain-of-function phenotype in both assay systems. In contrast, other Apaf-1 variants showed neutral or loss-of-function phenotypes. The depression-associated alleles thus have a common phenotype that is distinct from that of non-associated variants. This result suggests an etiologic role for enhanced apoptosis in major depression.

Alleles↗

PubMed2006

Supplementing drinking water with Solutein did not mitigate acute morbidity effects of porcine reproductive and respiratory syndrome virus in nursery pigs.

The objective of this study was to determine whether providing nursery pigs drinking water supplemented with spray-dried animal plasma (Solutein, American Protein Corporation Inc., Ankeny, IA) would reduce the detrimental impact of porcine reproductive and respiratory syndrome virus (PRRSV) infection. Sixty-four pigs were subjected to 1 of 4 treatment combinations (2 x 2 factorial arrangement) of Solutein [0 or 2.5% (wt/wt) in drinking water] and PRRSV (sterile medium or 5 mL of tissue culture infectious dose of high-virulence strain ATCC VR-2385). Pigs were provided the water treatments during a 1-wk period before inoculation as well as during a 2-wk period after inoculation. Growth performance was determined throughout the study, and several indicators of the immunological response to PRRSV and disease pathology were assessed in blood and tissue samples collected from pigs killed 7 or 14 d after inoculation. Before inoculation, pigs provided water supplemented with Solutein tended to eat less (P = 0.08) but tended to gain more BW (P = 0.13) than pigs provided tap water. Thus, Solutein markedly improved G:F (P < 0.01), after accounting for the DM provided by Solutein. Inoculation with PRRSV reduced ADG and ADFI (P < 0.01) irrespective of water treatment; however, the beneficial effects of Solutein on G:F persisted. Infection with PRRSV also reduced (P < 0.009) villus height and crypt depth in cranial, medial, and caudal segments of the small intestine and increased (P < 0.05) lung and spleen weight, the number of leukocytes in lung lavage fluid, and serum concentrations of interferon-gamma and IL-1beta regardless of water treatment. Collectively, these results indicate that supplementing water with spray-dried animal plasma improved feed efficiency but did not afford nursery pigs protection from the effects of PRRSV on growth and certain hematological traits.

Animals↗

PubMed2005

Alpha-tocopherol attenuates NFkappaB activation and pro-inflammatory cytokine production in brain and improves recovery from lipopolysaccharide-induced sickness behavior.

This study was conducted to determine if alpha-tocopherol facilitates recovery from lipopolysaccharide (LPS)-induced sickness behavior through a NFkappaB-dependent mechanism. In the first study, 3 daily intraperitoneal (i.p.) injections of alpha-tocopherol (20 mg) improved recovery from sickness behavior induced by i.p. injected LPS. Furthermore, alpha-tocopherol pretreatment attenuated LPS-activated NFkappaB and pro-inflammatory cytokine production in brain. In addition, inhibiting NFkappaB activity in the brain specifically by ICV injection of a NFkappaB decoy prior to LPS, significantly accelerated recovery from LPS-induced sickness behavior. Taken together, these data indicate alpha-tocopherol modulates sickness behavior and inflammatory cytokine production in the brain through an NFkappaB-dependent pathway.

Analysis of Variance↗

PubMed2005

Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system.

Acute cognitive impairment (i.e., delirium) is common in elderly emergency department patients and frequently results from infections that are unrelated to the central nervous system. Since activation of the peripheral innate immune system induces brain microglia to produce inflammatory cytokines that are responsible for behavioral deficits, we investigated if aging exacerbated neuroinflammation and sickness behavior after peripheral injection of lipopolysaccharide (LPS). Microarray analysis revealed a transcriptional profile indicating the presence of primed or activated microglia and increased inflammation in the aged brain. Furthermore, aged mice had a unique gene expression profile in the brain after an intraperitoneal injection of LPS, and the LPS-induced elevation in the brain inflammatory cytokines and oxidative stress was both exaggerated and prolonged compared with adults. Aged mice were anorectic longer and lost more weight than adults after peripheral LPS administration. Moreover, reductions in both locomotor and social behavior remained 24 h later in aged mice, when adults had fully recovered, and the exaggerated neuroinflammatory response in aged mice was not reliably paralleled by increased circulating cytokines in the periphery. Taken together, these data establish that activation of the peripheral innate immune system leads to exacerbated neuroinflammation in the aged as compared with adult mice. This dysregulated link between the peripheral and central innate immune system is likely to be involved in the severe behavioral deficits that frequently occur in older adults with systemic infections.

Aging↗

PubMed2005

Improved psychomotor performance in aged mice fed diet high in antioxidants is associated with reduced ex vivo brain interleukin-6 production.

Psychomotor performance is decreased in the aged. This study investigated the relationship between brain oxidative stress, interleukin-6 (IL-6) production by brain tissue ex vivo and psychomotor deficits during aging, and the effects of feeding an antioxidant-rich diet on ex vivo brain IL-6 production and motor function in aged mice. Male BALBc mice reared in SPF conditions and ranging in age from 3 to 24 months were studied. There was a precipitous decline in motor function after 12 months of age and an increase in brain lipid peroxidation and IL-6 production by coronal brain slices ex vivo. In another study, 12-month-old mice were fed diets formulated to provide a disparate range of antioxidants. At 18 months of age psychomotor coordination, motor learning, and ex vivo brain IL-6 production were evaluated. Mice fed an antioxidant-rich diet had improved psychomotor coordination compared to mice fed diet adequate or low in antioxidants. When mice were tested on successive days, only those fed adequate and high antioxidants exhibited motor learning. Analysis of IL-6 production by coronal brain slices indicated that as dietary antioxidants increased, IL-6 production decreased. Collectively, these data indicate that antioxidants improve psychomotor performance in aged mice, and suggest antioxidants may be useful for reducing brain IL-6 production, which has been shown to increase in aged mice.

Aging↗

PubMed2004

Interleukin-6 in the aging brain.

Astrocytes, microglia, and neurons express the cytokine interleukin-6 (IL-6), which in the brain has been suggested to reduce food intake, inhibit memory and learning, cause neurodegeneration, and exacerbate sickness behavior induced by other cytokines. Recent evidence indicates IL-6 levels are increased in brain of healthy aged animals, thus it may play a role in the neurophysiological manifestations of old age. The purpose of this brief report is to discuss the new evidence that suggests an age-related increase in brain IL-6 and the impact this inflammatory cytokine may have on "successful" aging.

Age Factors↗

PubMed2004

Vitamin E supplementation does not mitigate the acute morbidity effects of porcine reproductive and respiratory syndrome virus in nursery pigs.

The objective of this study was to determine whether feeding a vitamin E-rich diet would benefit nursery pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Sixty-four pigs were subjected to one of four treatment combinations (2 x 2 factorial) of dietary vitamin E (adequate or excess) and PRRSV (medium or inoculation with VR-2385 isolate P-129). Pigs were fed experimental diets during a 3-wk period before inoculation as well as during a 12-d period after inoculation. Growth performance was determined throughout the study, and lipid peroxidation in liver, glutathione peroxidase (GPX) activity in serum, circulating white blood cells, and serum interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) were determined in samples collected from pigs killed 4 or 12 d after inoculation. Infection by PRRSV (P < 0.001) induced a marked decrease in both ADFI and ADG, but neither the main effect of diet nor the diet x PRRSV interaction was significant. Neither diet nor PRRSV affected feed efficiency. At 12 d after inoculation, lipid peroxidation in liver and GPX activity in serum were lower in pigs fed excess vitamin E than in those fed adequate vitamin E (P < 0.01), suggesting that the diet high in vitamin E bolstered the antioxidant status of the pigs. However, PRRSV did not affect lipid peroxidation in liver or serum GPX activity, and the diet x PRRSV interaction was not significant. White blood cell counts were decreased and IFN-gamma, and IL-1beta were increased (P < 0.05) 4 and 12 d after inoculation in PRRSV-infected pigs, but neither diet nor the diet x PRRSV interaction was significant. Collectively, these results indicate that increasing antioxidant defenses by feeding high levels of vitamin E did not ameliorate the effects of PRRSV on decreased growth, leukopenia, and increased serum IL-1beta and IFN-gamma. Thus, feeding nursery pigs a diet high in vitamin E may not be useful for mitigating the acute morbidity effects of PRRSV infection.

Animals↗

PubMed2002

The concept of sickness behavior: a brief chronological account of four key discoveries.

Neurons do not have receptors to detect bacteria or viruses, yet the presence of these microorganisms can cause a sickness behavior syndrome that includes, e.g., fever, anorexia, and lethargy. Because the immune system has receptors capable of detecting these non-cognitive stimuli, how the immune system transmits a message to the brain has been studied to understand why behavior is altered in sick animals. The focus has been on several cytokines secreted by leukocytes; these include interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). These cytokines are secreted by activated mononuclear phagocytic cells, and numerous studies show that both peripheral and central injection of IL-1beta, IL-6, and TNF-alpha induce sickness behavior. Moreover, these cytokines and their receptors are present in the brain and inhibiting the secretion of cytokines or blocking their receptors in the brain blocks or abrogate the behavioral responses induced by inflammatory stimuli. Because the sickness behavior syndrome modulates the immune system and enhances recovery, the interplay between the immune system and central nervous system is an essential part of the overall host defense against pathogenic microorganisms. The purpose of this brief paper is to provide a chronological description of four critical advances that have led to the current understanding of how the immune system communicates with the brain to induce sickness behavior. Results from several key studies will be discussed, which showed that: (1) sickness behavior is a motivational state; (2) sickness behavior is a well-organized adaptive response to infection; (3) cytokines produced by activated leukocytes induce sickness behavior; and (4) cytokines transmit messages from the periphery to the brain using humoral and neural pathways.

Adaptation, Physiological↗

PubMed2002

Growth performance and whole-body composition of pigs experimentally infected with Mycoplasma hyopneumoniae.

Mycoplasma hyopneumoniae (Mh) is the primary infectious pathogen responsible for enzootic pneumonia in pigs. Although Mh is thought to impair growth performance, whole-body composition, and fat and protein accretion in pigs with pneumonia have not been reported and the mechanism through which Mh reduces growth is unknown. The objectives of this study were to evaluate the effects of Mh on growth performance, whole-body composition, and protein and fat accretion in nursery pigs and to determine whether Mh infection increases the expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). Sixty-four 2-wk-old Mh-free pigs were used (two trials) in a randomized complete block design. In each trial, two pigs were housed in each of 16 disease-containment chambers. At 4 wk of age, pigs were inoculated intratracheally with 3 mL of Mh broth (P5722-3, 10(7) cfu/mL) or sterile Friis culture medium. Clinical signs of disease and feed intake were monitored daily and body weight was determined weekly for 4 wk. Whole-body composition was determined from pigs killed 0, 14, and 28 d after inoculation, and the comparative slaughter technique was used to estimate protein and fat accretion. At death, gross lung lesions were quantified, and lung tissue was collected to verify the presence or absence of Mh, and to determine cytokine mRNA levels. Control pigs displayed no overt signs of infection and were Mh-negative and free of pulmonary lesions. Pigs inoculated with Mh showed pneumonic coughing (P < 0.005), were Mh-positive, and had pulmonary lesions that affected 4.5% (P < 0.01) and 14.1% (P < 0.001) of total lung surface area at 14 and 28 d, respectively, after inoculation. Ribonuclease protection assays revealed increased IL-1beta (P < 0.04) and TNF-alpha (P < 0.06) mRNA in lung tissue collected from a lesion site compared with tissue collected 10 cm from a lesion site or from control pigs. Interestingly, Mh did not depress weight gain or feed efficiency during any week of the 28-d study (P > 0.10). Moreover, Mh did not affect whole-body fat or protein accretion (P > 0.10). Thus, in spite of inducing disease and expression of inflammatory cytokines, Mh alone did not affect growth performance and whole-body composition of nursery pigs during the 4-wk experiment. The ability of pigs to contend with Mh may have resulted from the absence of other pathogens that generally co-exist with Mh under commercial conditions.

Animals↗

PubMed2001

A fatal case of Vibrio vulnificus presenting as septic arthritis.

Vibrio vulnificus is an invasive gram-negative bacillus that may cause necrotizing cellulitis, bacteremia, and/or sepsis. Although V vulnificus infection is uncommon, it is frequently fatal and is usually attributed to ingestion of raw shellfish or traumatic exposure to a marine environment; patients are also often found to have a hepatic disorder (cirrhosis, alcohol abuse, or hemochromatosis) or an immunocompromised health status, and most commonly present with septicemia or a wound infection. We describe a patient who presented with septic arthritis as the first clinical manifestation of a V vulnificus infection. The organism was subsequently identified in a synovial fluid aspirate.

Arthritis, Infectious↗

PubMed2001

IL-10 inhibits apoptosis of promyeloid cells by activating insulin receptor substrate-2 and phosphatidylinositol 3'-kinase.

IL-10 is well known to be a potent inhibitor of the synthesis of proinflammatory cytokines, but noninflammatory hemopoietic cells also express IL-10Rs. Here we show that IL-10 directly affects progenitor myeloid cells by protecting them from death following the removal of growth factors. Murine factor-dependent cell progenitors cultured in the absence of growth factors were 43 +/- 1% apoptotic after 12 h. Addition of IL-10 at a concentration as low as 100 pg/ml significantly reduced the apoptotic population to 32 +/- 3%. At 10 ng/ml, IL-10 caused a 4-fold reduction in the apoptotic population (11 +/- 1%). The anti-apoptotic activity of IL-10 was significantly inhibited with a neutralizing IL-10R Ab. Factor-dependent cell progenitor promyeloid cells expressed functional IL-10Rs, as assessed by precipitation of a 110-kDa protein with an Ab to the IL-10R and by the ability of IL-10 to activate Jak1 and Tyk2 and to phosphorylate tyrosine 705 on Stat-3. IL-10 increased tyrosyl phosphorylation of insulin receptor substrate-2 and stimulated the enzymatic activity of both phosphatidylinositol 3'-kinase and Akt. The anti-apoptotic activity of IL-10 was blocked by inhibition of phosphatidylinositol 3'-kinase. Wortmannin and LY294002 also totally inhibited activation of extracellular signal-related kinase (ERK)1/2 by IL-10. Direct inhibition of ERK1/2 with the mitogen-activated protein kinase/ERK kinase inhibitor PD98059 partially, but significantly, impaired the anti-apoptotic activity of IL-10. These data establish that activation of the IL-10R promotes survival of progenitor myeloid cells. This survival-promoting activity is totally due to IL-10 stimulating the insulin receptor substrate-2/PI 3-kinase/Akt pathway, which increases the anti-apoptotic activity of ERK1/2.

Apoptosis↗

PubMed2001

Tumor necrosis factor(alpha) and insulin-like growth factor-I in the brain: is the whole greater than the sum of its parts?

The cytokine tumor necrosis factor(alpha) (TNFalpha) and the hormone insulin-like growth factor-I (IGF-I) have both been shown to regulate inflammatory events in the central nervous system (CNS). This review summarizes the seemingly independent roles of TNFalpha and IGF-I in promoting and inhibiting neurodegenerative diseases. We then offer evidence that the combined effects of IGF-I and TNFalpha on neuronal survival can be vastly different when both receptors are stimulated simultaneously, as is likely to occur in vivo. We propose the framework of a molecular model of hormone-cytokine receptor cross talk in which disparate cell surface receptors share intracellular substrates that regulate neuronal survival.

Animals↗

PubMed2001

Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure.

INTRODUCTION: This study evaluated whether cyclosporine (CsA) could be eliminated from a sirolimus (Rapamune, rapamycin, SRL)-CsA-steroid (ST) regimen at 3 months. METHODS: This was an open-label study conducted in Europe, Australia, and Canada. Upon enrollment, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of sirolimus (troughs>5 ng/ml), CsA, and steroids. At 3 months+/-2 weeks, eligible patients were randomized (1:1) to remain on SRL-CsA-ST or to have CsA withdrawn and therapy continued with SRL (troughs 20-30 ng/ml)-ST. RESULTS: At 12 months, overall graft and patient survival were 89.1% and 94.9%, respectively. In the 430 (82%) randomized patients, there was no difference in graft survival (95.8% vs. 97.2%, SRL-CsA-ST vs. SRL-ST) or patient survival (97.2% vs. 98.1%, respectively). The incidence of biopsy-confirmed primary acute rejection was 13.1% during the prerandomization period. After randomization, the acute rejection rates were 4.2% and 9.8% for SRL-CsA-ST and SRL-ST, respectively (P=0.035). Renal function (calculated glomerular filtration rate, 57 vs. 63 ml/min, P<0.001) and blood pressure significantly improved when CsA was withdrawn. Hypertension, CsA nephrotoxicity, hyperuricemia, and Herpes zoster occurred statistically more frequently in patients remaining on CsA, whereas thrombocytopenia, abnormal liver function tests, and hypokalemia were reported more often for SRL-ST therapy. CONCLUSION: Sirolimus, CsA, and steroids for 3 months posttransplant, followed by elimination of CsA, is a safe and effective alternative to continuous therapy with sirolimus, CsA, and steroids that can result in better renal function and lower blood pressure.

Adolescent↗

PubMed2001

Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation.

BACKGROUND: Daclizumab (Zenapax, Roche Pharmaceuticals), a humanized monoclonal antibody directed against the alpha chain of the interleukin 2 receptor, has been shown to reduce the incidence of acute rejection at 6 months after renal transplantation in two phase III clinical trials. This report presents the combined 1- and 3-year outcomes of kidney transplant recipients who participated in these two phase III clinical trials. METHODS: Data from two multicenter, randomized, placebo-controlled trials were evaluated with regard to graft survival, patient survival, incidence of malignancies (including lymphoma), renal function (serum creatinine and glomerular filtration rate [GFR]), and current maintenance immunosuppressive regimen. In addition, the impact of acute rejection and acute rejection requiring treatment with antilymphocyte therapy upon 3-year graft survival was evaluated. Daclizumab was compared to placebo on a background of cyclosporine (CsA), azathioprine, and corticosteroids (triple therapy, TT) or CsA and corticosteroids (double therapy, DT). RESULTS: Treatment with daclizumab in the pooled analysis demonstrated a significant reduction in the incidence of biopsy-proven acute rejection episodes at 12 months posttransplant (43% vs. 28%, P<0.001). The 3-year graft survival was not significantly different between placebo and daclizumab-treated patients in the TT trial (83% vs. 84%) or in the DT trial (78% vs. 82%). Pooled patient survival was excellent in both placebo- (91%) and daclizumab- (93%) treated patients. The incidence of malignancies or posttransplant lymphoproliferative disorder (PTLD) in placebo- versus daclizumab-treated groups was comparable in both clinical trials. Renal function was similar between placebo- and daclizumab-treated groups in both the TT and DT trials. The occurrence of delayed graft function, acute rejection requiring antilymphocyte therapy at 6 months, and acute rejection at 12 months posttransplant were associated with decreased graft survival rates at 3 years posttransplant. CONCLUSIONS: The beneficial effect of daclizumab prophylaxis upon the incidence of acute rejection after renal transplant with TT or with DT was not associated with adverse clinical sequelae, including the development of PTLD, at 3 years posttransplant. There was no beneficial effect of daclizumab on graft survival at 3 years, but the trial was inadequately powered to detect this. Both studies showed excellent graft and patient survival at 3 years.

Acute Disease↗

PubMed2001

Effect of cold ischemic time and HLA matching in kidneys coming from "young" and "old" donors: do not leave for tomorrow what you can do tonight.

BACKGROUND: Kidneys from older donors are likely to have a lower nephron mass. Nevertheless they constitute a valuable source of kidney allografts. Long cold ischemic time (CIT), with or without delayed graft function (DGF), has been associated with reduced graft survival. The aim of this study was to review the experience of a single UK center to assess the interaction of cold storage time, donor age, organ exchange, and HLA-DR mismatching on short- and long-term survival. METHODS: We analyzed 788 first cadaver kidney transplants that were performed in our center from 1990 to 1997 and had complete data available. A donor age of 55 years was the cutoff age for "old" and "young" donor kidneys. The primary outcome measured was graft failure from any cause. RESULTS: There were 132 grafts from donors 55 years or older (16.7%), with 76.8% of the kidneys implanted after >20 hr of CIT. Kidney grafts from donors older than 55 years had worse graft survival than grafts from donors younger than 55 (87% vs. 78% at 1 year and 80% vs. 58% at 5 years after transplant, P=0.0001). A CIT of >20 hr significantly reduced graft survival (91% vs.74.3% at 5 years after transplant, P=0.0002) in the young donor group and was associated with an overall graft survival in the old donor group of 57.5% at 5 years. In the same group, ignoring the HLA-DR mismatching to achieve shorter CIT, the predicted initial cost on graft survival at 1 year would have been 3.7% but would have increased to 9% 5 years after transplant. For young donors a CIT of >20 hr had a cost of approximately 18% at 5-year graft survival, far higher than a single DR mismatch. Occurrence of DGF decreased survival in both short (P=0.001) and long (P=0.00001) CIT groups. CONCLUSION: Forming local alliances (common recipient lists) and minimizing delays within the hospital might reduce CIT and DGF while achieving excellent HLA matching. This should improve significantly the outcome of both old and young donor kidney grafts.

Aging↗

PubMed2001

Regulation of interleukin-6 gene expression in brain of aged mice by nuclear factor kappaB.

Interleukin-6 (IL-6) is increased in brain of aged mice. The purpose of this study was to determine if binding of nuclear factor kappaB (NFkappaB) to the IL-6 promoter is responsible for the age-related increase in brain IL-6. In an initial study, the effect of age on IL-6 in brain was verified as IL-6 protein was increased in brain of aged mice compared to adult and juvenile mice. Competitive RT-PCR showed that IL-6 mRNA concentration was at least 4-fold higher in aged brain compared to adult brain. Next, binding of the transcription factor NFkappaB to the IL-6 promoter in brains of 1-, 6-, and 24-month-old mice was determined. Electrophoretic mobility shift assay showed that NFkappaB activity was increased in aged brain compared to adult and juvenile brain. Moreover, glial cells cultured from aged mice showed more NFkappaB DNA-binding activity and more IL-6 mRNA and protein expression than glia from adults. However, incubating glia from aged mice in the presence of kappaB decoy inhibited these effects of age. The same was observed in vivo as intracerebroventricular injection of kappaB decoy in aged mice decreased NFkappaB activity and IL-6 mRNA and protein in brain. These results show that the DNA-binding activity of NFkappaB is increased in the brain of aged mice and that at least one consequence is increased expression of IL-6.

Age Factors↗

PubMed2001

Association of polymorphisms in the human interferon-gamma and interleukin-10 gene with acute and chronic kidney transplant outcome: the cytokine effect on transplantation.

BACKGROUND: Our group has previously described five different size alleles of an interferon (IFN)-gamma microsatellite. Analyzing this polymorphism, this study correlated high IFN-gamma production with a 12 CA repeat allele (allele 2). Further, our group has described interleukin (IL)-10 polymorphism defining in vitro high and low IL-10 producer status. METHODS: Samples from 88 of 115 consecutive cadaveric renal transplants were used to define polymorphism of both IFN-gamma and IL-10. Patients were separated into high and low genotypes based on the previously reported association between certain genotypes and in vitro production. Graft survival, acute rejection, and serum creatinine at 5 years were analyzed for comparison between groups. RESULTS: The genotype associated with high IFN-gamma production was found in 70 patients. The incidence of acute rejection was 54.3% in the high IFN-gamma genotype group, compared with 44.4% in the low IFN-gamma group. Requirement for antithymocyte globulin therapy was greater in the high IFN-gamma group (odds ratio [OR]=2.5). Among HLA-DR-mismatched patients, IFN-gamma genotype was more strongly associated with rejection (OR=2.86). In the cyclosporine monotherapy subgroup, patients with high IFN-gamma genotype had a 61% incidence of rejection compared with only 20% in the low IFN-gamma genotype patients (OR=3.06). Graft survival was similar between the two groups. When the analysis was controlled for the presence of delayed graft function, 40.5% of the high IFN-gamma genotype patients had serum creatinine levels above 200 micromol/L compared with only 14.3% of the low IFN-gamma genotype recipients at 5 years after transplantation (P=0.05). The high IL-10 genotype was shown to be associated with better graft function at 5 years (75 vs. 50%, P=0.09). CONCLUSION: In this study we have shown that high producer genotype for IFN-gamma may have an influence on acute rejection of kidney transplants, particularly in patients on cyclosporine monotherapy. It is also associated with worse long-term graft function. On the contrary high IL-10 production may have a long-term protective effect.

Acute Disease↗