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PubMed2004

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans.

There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1+/-4.5 vs 37.1+/-6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3+/-4.3 vs 51.2+/-6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.

Adult↗
PubMed1999

Review article: targeting TNF alpha as a key cytokine in the inflammatory processes of Crohn's disease--the mechanisms of action of infliximab.

Crohn's disease is a chronic, debilitating gastrointestinal disorder in which a variety of cellular processes and pro-inflammatory mediators influence the pathogenesis of the disease. Although the potential roles and functions of the pro-inflammatory mediators continue to be debated, several mediators, specifically tumour necrosis factor-alpha, have been clearly identified as having a pivotal role in the inflammation of the bowel mucosa of these patients. Therapies specifically focusing on the inflammatory process underlying Crohn's disease have the potential for providing disease modification and prolonged remission. Infliximab, an antitumour necrosis factor-alpha monoclonal antibody, has been demonstrated to neutralize tumour necrosis factor-alpha and restore and reset the immunological dysbalance of the inflamed mucosa. Preliminary studies with infliximab suggested that treatment resulted in a rapid and almost complete inhibition of multiple inflammatory pathways. In clinical studies of infliximab, patients with Crohn's disease achieved rapid reduction in clinical signs and symptoms, substantiated by both endoscopic and microscopic evaluation.

Animals↗
PubMed1998

IgG-mediated anaphylaxis via Fc gamma receptor in CD40-deficient mice.

Anaphylaxis denotes an immediate hypersensitivity reaction to allergen, exclusively mediated by IgE antibodies. However, IgE antibodies do not explain all the syndromes that are encountered. We investigated potent IgG-mediated anaphylaxis in CD40-deficient mice that lack the immunoglobulin class switching for T cell-dependent antigens. Immunization with ovalbumin did not induce either humoral responses of IgG, IgA, and IgE, or systemic anaphylaxis in CD40-deficient mice. Although systemic anaphylaxis by active immunization was not observed in CD40-deficient mice, both passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis assessed by mouse blood pressure monitoring with cervical artery catheterization did take place when antigen-specific IgG was transferred and then antigen challenge given. Further, to investigate the inflammatory pathway of IgG-mediated immediate hypersensitivity reactions, we focused on the Fc gamma receptor (Fc gammaR) function. Pretreatment of the mice with the anti-Fc gammaRII/Fc gammaRIII MoAb clearly blocked the response of PCA and passive systemic anaphylaxis, suggesting that they were initiated through Fc gammaR. In conclusion, we directly demonstrate the IgG-mediated anaphylaxis and its triggering mechanism through Fc gammaR in in vivo conditions. In addition to IgE-mediated anaphylaxis, IgG-mediated anaphylaxis should be considered and the blocking of Fc gammaR would provide one of the therapeutic targets for the control of IgG-mediated hypersensitivity diseases.

Anaphylaxis↗
PubMed2003

Hypertension increases expression of growth factors and MHC II in chronic allograft nephropathy.

BACKGROUND: Hypertension of the recipient is strongly associated with chronic allograft nephropathy. It is unclear, however, whether hypertension is the cause or the consequence of chronic allograft nephropathy. METHODS: The present study was performed in the Fisher to Lewis rat kidney transplant model. Transplanted rats (N = eight in each group) received either no treatment or were made hypertensive by administration of deoxycorticosteron acetate (DOCA) and salt. Proteinuria and systolic blood pressure was measured monthly, grafts were harvested at 3 and 6 months for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and for immunohistology. RESULTS: Systolic blood pressure was markedly elevated in rats receiving DOCA/salt. Allografts of hypertensive animals contained significantly more cells expressing the proliferating cell nuclear antigen compared to isografts and to allografts from normotensive animals (P < 0.05). Histologic staining and mRNA expression of major histocompatibility complex (MHC) II was markedly increased in allografts of hypertensive animals compared to all other groups (P < 0.05). Expression of mRNA for platelet-derived growth factor-B (PDGF-B), transforming growth factor-beta (TGF-beta) and collagen was higher in allografts than in isografts and was highest in hypertensive animals. CONCLUSION: We conclude that hypertension augments the expression of growth factors in the allograft possibly aggravating the intimal hyperplasia observed in chronic allograft nephropathy. By increasing the expression of MHC II antigens, hypertension may render the allograft more susceptible to alloantigen-dependent damage. Hypertension and alloantigen-dependent factors appear to exert additive or synergistic effects on inflammatory pathways leading to graft injury.

Animals↗
PubMed2003

Cross-linked fibrin degradation products (D-dimer), plasma cytokines, and cognitive decline in community-dwelling elderly persons.

OBJECTIVES: To investigate the effect of coagulation and inflammatory pathway activation on future cognitive decline in older persons. DESIGN: Prospective cohort study. SETTING: Rural and urban communities in North Carolina. PARTICIPANTS: Community-dwelling older people enrolled in the Duke Established Populations for Epidemiologic Studies of the Elderly in 1986. MEASUREMENTS: In 1992, blood was drawn for assay of D-dimer (1,723 subjects), Interleukin-6 (1,726 subjects), and other cytokines (1,551 subjects). Cognitive and functional assessments were performed in 1986, 1989, 1992, and 1996. Cognition was measured using the Short Portable Mental Status Questionnaire. RESULTS: Cognitive decline over a 4-year period was significantly correlated (P<.001) with D-dimer, age, race, and physical performance status as measured using the Rosow-Breslau and Nagi instruments. After controlling for demographics, functional status, and comorbidities, D-dimer remained predictive of cognitive decline. Proinflammatory cytokines were not associated with current cognitive status in cross-sectional analyses or with incident cognitive decline in prospective analyses. CONCLUSION: In a large sample of community-dwelling elders, higher levels of D-dimer were predictive of cognitive decline over a 4-year period. No clinically significant associations were found between age-related peripheral cytokine dysregulation and cognition.

Aged↗
PubMed2003

Effects of tacrolimus on ischemia-reperfusion injury.

In addition to efficacious immunosuppression for the benefit of organ transplantation, tacrolimus has diverse actions that result in amelioration of ischemia-reperfusion injury. Knowledge is accumulating rapidly on the mechanisms through which tacrolimus exerts these cytoprotective effects, including alterations in microcirculation, free radical metabolism, calcium-activated pathways, inflammatory cascades, mitochondrial stability, apoptosis, stress-response proteins, and tissue recovery. Within the nucleus, actions mediating the effects of tacrolimus appear to be dominantly influenced by interactions with the transcription factor, nuclear factor-kappaB. Because tacrolimus is a cornerstone agent in immunosuppression regimens throughout the world and knowledge of its cellular mechanisms is evolving, it is important to update the clinical literature with this information. We reviewed the published literature with intent to portray the interactions of tacrolimus in the intricate cellular mechanisms initiated by ischemia and reperfusion.

Adenosine Triphosphate↗
PubMed2003

Overview of tropical nephrology.

Tropical nephrology covers renal diseases commonly seen in the tropics and elsewhere and specific tropical renal diseases seen mostly or only in the tropical area. Emphasis in this article is placed on the latter category, which includes renal involvement in tropical infectious diseases, natural toxin poisoning, and environmental renal problems. Pathologically, all renal structures can be affected. There is, therefore, a broad spectrum of pathologic changes, and clinical renal manifestations vary from mild urinary sediment changes to acute renal failure. Inflammatory processes plays an essential role in the pathogenesis of renal involvement in infection and toxin groups. Both models share the same inflammatory pathways through cytokines, chemokines, and mediators. Hemodynamic alterations, immune response, and direct nephrotoxicity are involved in the development of renal lesions.

Female↗
PubMed2002

Adiponectin--its role in metabolism and beyond.

Adiponectin is a recently identified adipose tissue-derived protein (adipocytokine) with important metabolic effects. It is exclusively expressed in adipose tissue and released into the circulation. Adiponectin expression and/or secretion is increased by insulin like growth factor-1 and ionomycin, and decreased by tumor necrosis factor-alpha, glucocorticoids, beta-adrenergic agonists and cAMP. Data for insulin are somewhat inconclusive. Moreover, adiponectin expression and secretion are increased by activators of peroxisome proliferator-activated receptor (PPAR)-gamma. Besides inhibiting inflammatory pathways, recombinant adiponectin increases insulin sensitivity and improves glucose tolerance in various animal models. This insulin-sensitizing effect appears to be mostly attributable to enhanced suppression of glucose production, but beneficial effects on muscle cannot be excluded. In humans, plasma adiponectin concentrations exceed those of any other hormone by a thousand times; they decrease with obesity and are positively associated with whole-body insulin sensitivity. Therefore, low adiponectin may contribute to the decrease in whole-body insulin sensitivity that accompanies obesity. Furthermore, there is increasing evidence that genetic variants in the adiponectin gene itself and/or in genes encoding adiponectin-regulatory proteins--such as PPAR-gamma--may be associated with hypoadiponectinemia, insulin resistance and type 2 diabetes. This suggests that adiponectin may reflect PPAR-gamma activity in vivo. Finally, reversal or alleviation of hypoadiponectinemia may represent a target for development of drugs improving insulin sensitivity and glucose tolerance.

Adiponectin↗
PubMed2005

Immunoglobulin levels and lymphocyte subsets following cardiac operations: further evidence for a T-helper cell shifting.

BACKGROUND: Recent data indicate that cardiac surgery with cardiopulmonary bypass (CPB) results in an imbalance of T-helper cell subsets towards the anti-inflammatory pathway mediating humoral immune response. However, little is known about immunoglobulin levels as an important part of humoral immune response after CPB. Therefore, the objectives of this study were 1) to elucidate the effects of CPB on perioperative immunoglobulin levels, and 2) to find out if alterations in lymphocyte subsets are related to these findings. METHODS: Blood samples from 83 patients undergoing elective cardiac operation were taken preoperatively (d0), on the first (d1), third (d3), and fifth day (d5) after operation. Levels of immunoglobulin (Ig) E, IgM, and IgG, including the subclasses IgG 1 - 4, were measured. IgG2/IgE-ratio was used as indicator for TH1/TH2 shifting, and production of tetanus antibodies (AB) was investigated as an in vivo parameter of humoral immune reaction. The number and percentage of T- and B-lymphocyte subsets were assessed in a subgroup of 50 patients to answer the second question. RESULTS: Clinically, no mortality or major morbidity were observed. IgE levels did not change until d3 and increased significantly on d5. In contrast, both IgG and IgM levels decreased significantly on d1. While IgM returned to baseline (BL) on d5, IgG levels remained below BL until d5. IgG2/IgE-ratio decreased significantly on d1, reached its nadir on d3 and remained depressed until d5. The number of T-lymphocytes decreased on d1 as well as the number of B-cells. T-cells returned to BL on d5, B-cells on d3. However, while the percentage of T-cells decreased on d1, the percentage of B-cells increased. The percentage of T-cells returned to BL on d3, and B-cell percentage returned to BL on d5. Tetanus AB production did not change until d5 when it increased significantly. CONCLUSIONS: 1) Increase of IgE and tetanus AB production indicate that humoral immune response is not affected by CPB, but possibly even enhanced. The relative increase of B-cells is in line with this hypothesis. 2) Postoperative changes in immunoglobulin levels provide further evidence for a TH1/TH2-shifting. 3) The transient deficit in IgM-and IgG levels did not result in clinically adverse events. Thus, therapeutic intervention appears not to be required.

Adult↗
PubMed1990

Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis.

The syndromes of purpuric lesions associated with a thrombotic mechanism are very rare in the general population. Dermal vascular thrombosis, however, can be devastating and associated with significant morbidity and mortality. These syndromes share common features in their clinical course, pathogenesis, and histology. Although these syndromes can be initiated by either the hemostatic or inflammatory pathways, both pathways center around perturbations of the endothelial cell, which promote thrombosis. If animal models or better testing can be developed, enhanced appreciation of mechanisms underlying purpura fulminans may be deduced. Characterization of the pathophysiology may then allow directed treatment modalities that could limit the course of these syndromes and reduce morbidity and mortality.

Endothelium, Vascular↗
PubMed1999

Plasma levels of selectins and interleukins in cardiovascular surgery using cardiopulmonary bypass.

BACKGROUND: Cardiovascular surgery with cardiopulmonary bypass (CPB) leads to activation of a variety of inflammatory pathways, including the release of cytokines and selectins. METHODS: In 20 patients undergoing elective coronary artery bypass grafting, plasma levels of interleukins IL-2, -6, -8, -10, -12 and of P-, E-, and L-selectins were measured at eight time points before, during, and after CPB using a standardized ELISA technique. RESULTS: IL-2 plasma levels decreased significantly after the start of CPB and remained low until the second postoperative day. IL-6 and IL-8 levels increased significantly after weaning off CPB, with mean peak values six hours postoperatively. Very low IL-10 plasma levels were detectable preoperatively. They remained low during CPB and peaked significantly after weaning off CPB until skin closure. The IL-12 levels decreased after weaning off CPB (p < 0.05) until 6 hours postoperatively. The plasma levels of P-selectin showed no alterations, but concentrations of E- and L-selectin decreased after the start of CPB (p < 0.05). There were no adverse postoperative events. CONCLUSIONS: The results of our study demonstrate a dysregulation of cytokine and selectin production during and up to 48 h after CPB, which may be a "normal" stress reaction to CPB.

Adult↗
PubMed2003

Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease.

Previous studies in Creutzfeldt-Jakob disease (CJD) have shown that myeloid cells in the periphery as well as derivative microglial cells in the brain are infectious. Microglia can show an activated phenotype before prion protein (PrP) pathology is detectable in brain, and isolated infectious microglia contain very little PrP. To find whether a set of inflammatory genes are significantly induced or suppressed with infection, we analyzed RNA from isolated microglia with relevant cDNA arrays, and identified approximately 30 transcripts not previously examined in any transmissible spongiform encephalopathy. This CJD expression profile contrasted with that of uninfected microglia exposed to prototypic inflammatory stimuli such as lipopolysaccharide and IFN-gamma, as well as PrP amyloid. These findings underscore inflammatory pathways evoked by the infectious agent in brain. Transcript profiles unique for CJD microglia and other myeloid cells provide opportunities for more sensitive preclinical diagnoses of infectious and noninfectious neurodegenerative diseases.

Animals↗
PubMed2005

Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation.

Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with beta-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer. Likewise, Lrh-1+/- mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane. LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-alpha. Reciprocally, decreased LRH-1 expression in Lrh-1+/- mice attenuates TNF-alpha expression. Compared with normal human colon, expression and subcellular localization of LRH-1 is significantly altered in neoplastic colon. In combination, these data suggest a role of LRH-1 in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways.

Animals↗
PubMed2001

Elevation of serum soluble E-selectin and VCAM-1 in severe asthma.

OBJECTIVE: To investigate the significance of circulating adhesion molecules associated with leucocyte-endothelial cell interactions in asthma, serum levels of soluble E (sE)-selectin, soluble P (sP)-selectin, soluble L (sL)-selectin, and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in mild, moderate and severe asthma. METHOD: Serum levels of sE-selectin, sP-selectin, sL-selectin, and sVCAM-1 were measured in 32 women with asthma and 30 healthy donors using an enzyme-linked immunosorbent assay method. Twenty patients were suffering from severe asthma, and 12 from mild/moderate asthma. RESULTS: Serum sE-selectin and sVCAM-1 levels from patients with asthma were significantly higher than those observed in healthy donors (p < 0.01). The levels of sP-selectin were the same as those of controls. The level of sE-selectin exhibited an important increase in the severe asthmatic patients compared with mild/moderate asthma (p < 0.01). The sVCAM-1 level was increased in severe asthma when compared with healthy controls. There was no correlation between the levels of soluble selectins and the age of the patients. A significant correlation was found between sE-selectin and sVCAM-1 levels. CONCLUSION: These data indicate that circulating soluble forms of the selectins may have different kinetics during the clinical course of asthma, suggesting that they may reflect different inflammatory pathways in severe asthma. Both sVCAM-1 and sE-selectin may be useful immunological markers for monitoring disease activity in asthma.

Adult↗
PubMed2004

Early induction of interferon-responsive mRNAs in Creutzfeldt-Jakob disease.

Foreign infectious agents typically evoke a host immune response. In scrapie and Creutzfeldt-Jakob disease (CJD), no immune response has been detectable. However, many latent or persistent viruses evade immune recognition but still activate inflammatory pathways. Unique microglial responses in late CJD infection that could be part of a host defense mechanism were previously delineated, although changes secondary to neurodegeneration could not be excluded. Data here show these microglial transcriptional changes are detectable in CJD brain beginning at 30 days after innoculation. In addition, 10 other interferon-sensitive genes were similarly upregulated at very early stages of infection. These responses occurred well before abnormal prion protein (PrP) and clinical signs of CJD were detectable. Further analyses in very pure microglia from CJD brain suggested the CJD agent activated signaling pathways distinct from those induced by amyloidogenic proteins (including abnormal PrP). Although increases in interferon-alpha or -beta transcript levels were not seen in cultures or in whole brain, CJD microglia exhibited a potentiated interferon response when challenged with double-stranded RNA. The induction of interferon-sensitive genes without appreciable interferon synthesis was strikingly similar to that seen in some viral infections. These data suggest the CJD agent is recognized as a foreign virus-like entity. Moreover, the early reactive gene expression profiles described here may be useful in preclinical diagnosis.

Animals↗
PubMed1999

Secretory leukocyte protease inhibitor suppresses the inflammation and joint damage of bacterial cell wall-induced arthritis.

Disruption of the balance between proteases and protease inhibitors is often associated with pathologic tissue destruction. To explore the therapeutic potential of secretory leukocyte protease inhibitor (SLPI) in erosive joint diseases, we cloned, sequenced, and expressed active rat SLPI, which shares the protease-reactive site found in human SLPI. In a rat streptococcal cell wall (SCW)-induced model of inflammatory erosive polyarthritis, endogenous SLPI was unexpectedly upregulated at both mRNA and protein levels in inflamed joint tissues. Systemic delivery of purified recombinant rat SLPI inhibited joint inflammation and cartilage and bone destruction. Inflammatory pathways as reflected by circulating tumor necrosis factor alpha and nuclear factor kappaB activation and cartilage resorption detected by circulating levels of type II collagen collagenase-generated cleavage products were all diminished by SLPI treatment in acute and chronic arthritis, indicating that the action of SLPI may extend beyond inhibition of serine proteases.

Amino Acid Sequence↗
PubMed2001

Mannose-binding lectin regulates the inflammatory response of human professional phagocytes to Neisseria meningitidis serogroup B.

The influence of the innate immune protein mannose-binding lectin (MBL) on the response of human phagocytes to Neisseria meningitidis was investigated. MBL increased the association of killed meningococci with neutrophils, monocytes, and macrophages by increasing the proportion of cells that recognized bacteria. MBL down-regulated the normal change in expression of the leukocyte adhesion molecules CD11b and CD62L. In an ex vivo model, the addition of MBL to the blood of MBL-deficient donors influenced the production of monocyte-derived inflammatory cytokines. The addition of high concentrations of MBL (>6 microg/mL) profoundly decreased the production of interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha by monocytes in response to meningococci, whereas lower concentrations enhanced the production of IL-6 and IL-1beta. These results suggest that MBL not only is involved in complement activation but also is a potent regulator of inflammatory pathways and, as such, may affect the severity of meningococcal disease.

CD11 Antigens↗
PubMed2002

Proinflammatory cytokines in the course of Mycobacterium tuberculosis-induced apoptosis in monocytes/macrophages.

Mycobacterium tuberculosis (MTB) can induce apoptosis in monocytes/macrophages both in vitro and in vivo, and this phenomenon is associated with mycobacterial survival. The present study addresses the possibility that apoptotic and inflammatory pathways could coexist through a caspase-1-mediated mechanism. In this context, a caspase-1 inhibitor (YVAD), but not caspase-3 (DEVD) or caspase-4 (LEVD) inhibitors, was able to strongly inhibit MTB-induced apoptosis. Moreover, caspase-1 activity was confirmed by the increased maturation of interleukin (IL)-1beta. Of interest, IL-1beta and tumor necrosis factor (TNF)-alpha were produced massively in the course of infection, and both were inhibited by YVAD pretreatment. To determine whether TNF-alpha was produced actively by apoptotic cells, the intracytoplasmatic cytokine content and apoptotic phenotype were analyzed at the single-cell level. Results showed a progressive increase of TNF-alpha production in annexin V-positive cells. These results indicate that MTB-induced apoptosis is associated with proinflammatory cytokine production.

Apoptosis↗