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Biomedical subjects

I Kushner

Publications and source records attributed to I Kushner.

At least 19 recordsLinked to original sources
PubMed2002

Evidence from clinical trials and long-term observational studies that disease-modifying anti-rheumatic drugs slow radiographic progression in rheumatoid arthritis: updating a 1983 review.

Earlier reports, including a comprehensive 1983 review, had indicated that slowing of radiographic progression was relatively unusual in treatment of rheumatoid arthritis (RA) using traditional disease modifying anti-rheumatic drugs. However, in recent years, slowing of radiographic progression has been documented in a number of clinical trials, as well as long-term observational studies, with use of (in alphabetical order) adalimumab, anakinra, corticosteroids, cyclophosphamide, cyclosporin, etanercept, gold salts, infliximab, leflunomide, methotrexate and sulphasalazine. At this time, disease modification is a realistic goal in the clinical care of patients with RA. Documentation of improved long-term outcomes requires long-term observational data over 5-20 yr to supplement data from randomized controlled clinical trials over 6-24 months.

Antirheumatic Agents↗
PubMed2001

Transactivation of C-reactive protein by IL-6 requires synergistic interaction of CCAAT/enhancer binding protein beta (C/EBP beta) and Rel p50.

We have previously found that overexpression of the Rel protein p50 stimulated C-reactive protein (CRP) expression in Hep 3B cells and that p50 could bind to a nonconsensus kappaB site overlapping the CCAAT/enhancer binding protein (C/EBP) binding site centered at position -53 on the CRP promoter. Accordingly, we employed EMSA to investigate possible cooperation between p50 and C/EBP proteins using an oligonucleotide probe (-63/-41) derived from the CRP promoter and containing both C/EBP and p50 binding sites. Abs to p50, but not to p65, decreased formation of C/EBPbeta-containing complexes in nuclei of IL-6-treated cells, indicating that ternary complexes containing C/EBPbeta and p50 are formed on the CRP promoter. Depletion of free Rel proteins by pretreatment of nuclear extracts with a kappaB consensus oligonucleotide markedly decreased formation of C/EBP complexes, indicating that Rel proteins are required for formation of such complexes. Overexpression of p50 in transient cotransfection studies using the proximal CRP promoter (-125/+9) linked to a luciferase reporter caused a 3-fold increase of luciferase activity, while C/EBPbeta overexpression caused an 18-fold increase; simultaneous overexpression of both transcription factors increased luciferase activity approximately 600-fold. Mutation of either the C/EBP binding site or the p50 binding site drastically reduced the effects of overexpressed transcription factors. Taken together, our findings indicate that binding of Rel p50 to the nonconsensus kappaB site enhances and stabilizes binding of C/EBPbeta to the CRP promoter and that binding of both C/EBPbeta and p50 to their overlapping cognate sites is required for induction of CRP expression by IL-6.

Binding Sites↗
PubMed2001

Can a nutrition intervention improve albumin levels among hemodialysis patients? A pilot study.

OBJECTIVE: To determine the effect of a tailored intervention on albumin levels among hemodialysis patients. DESIGN: Randomized controlled trial. SETTING: Eight freestanding chronic hemodialysis units in northeast Ohio. SUBJECTS: Eighty-three randomly selected adult patients who had been on dialysis for at least 6 months and had a mean albumin <3.7 g/dL (bromcresol green method) or <3.4 g/dL (bromcresol purple method) for the last 3 months. To better elucidate the feasibility and outcomes of the intervention, we selected more intervention than control patients. INTERVENTION: Dietitians of the 52 intervention patients determined whether any of the following potential barriers to adequate protein nutrition were present for each patient: (1) poor knowledge of protein-containing foods, (2) poor appetite, (3) needing help shopping or cooking, (4) low fluid intake, and (5) inadequate dialysis. Depending on the specific barriers present, the dietitians (1) educated patients on protein-containing foods, (2) recommended snacks for which patients had preserved appetite, (3) helped set up social supports, (4) provided recommendations on fluid intake, and/or (5) arranged for improved dialysis. Dietitians of the 31 control patients continued to provide usual care. MAIN OUTCOME MEASURES: Change in albumin after 6 months, stratified as minimal change (less than.25 g/dL increase or decrease), moderate improvement (.25 to.49 g/dL increase), and large improvement (increase of .50 g/dL or more). To examine the role of inflammatory states, we also determined serum C-reactive protein levels at the beginning and end of the trial. RESULTS: Among intervention patients, 29% had a minimal change in albumin, 44% had a moderate improvement, and 27% had a large improvement. Among control patients, 74% had a minimal change in albumin, 19% had a moderate improvement, and 6% had a large improvement (P <.001 for comparison of intervention and control subjects). About 60% of subjects had high baseline C-reactive protein levels (> 10 mg/L). However, there was little relationship between change in albumin and either baseline C-reactive protein levels or changes in C-reactive protein levels (P = .83). CONCLUSION: A nutrition intervention tailored to patient-specific barriers resulted in improved albumin levels even among patients with high C-reactive protein levels. Further work is needed to refine and test this intervention on a larger sample.

Aged↗
PubMed2001

C-reactive protein elevation can be caused by conditions other than inflammation and may reflect biologic aging.

Epidemiologic studies have revealed that minimal acute-phase changes predict poor prognoses in many conditions and predict disability and mortality in the elderly. These findings have usually been interpreted to indicate that inflammatory processes of some kind play a role in these situations. In fact, a minimal acute-phase response does not necessarily establish the existence of an inflammatory process but may also reflect a variety of noninflammatory states, including obesity, sleep disturbance, depression, chronic fatigue, and low levels of physical activity. I propose that a minimal acute-phase response may also be a marker of biologic aging, a condition known to predispose to poor prognoses and to death.

Aging↗
PubMed2000

The Rel family member P50 mediates cytokine-induced C-reactive protein expression by a novel mechanism.

Transcription of C-reactive protein (CRP) in Hep 3B cells is induced by IL-6, acting through C/EBP isoforms and STAT3. IL-1beta, which alone has no effect, greatly enhances IL-6-induced transcription by unknown mechanisms. Because IL-1beta activates the NF-kappaB system, we explored the effects of overexpressed Rel family members on CRP expression. Unexpectedly, transactivation assays in transiently transfected Hep 3B cells showed p50 overexpression to markedly induce CRP transcription, acting in a region 3' to -86. In the presence of overexpressed p50, IL-1beta induced a 3-fold increase in CRP expression, and responses to IL-6 and to IL-6 plus IL-1beta were 4-fold greater than seen in cells without p50 overexpression. In contrast, overexpressed p65 abolished CRP induction by p50 and by cytokines. EMSA studies demonstrated that recombinant p50 bound to a nonconsensus kappaB site overlapping the proximal C/EBP binding site on the CRP promoter. Mutation of a polypyrimidine tract in the p50-binding site inhibited the transactivating effect of cytokines. P50- but not p65-containing dimers were found in nuclei of Hep 3B cells 18 h after stimulation with IL-1beta, when C/EBPbeta is greatly activated, in the presence or absence of IL-6. These findings suggest that IL-1beta induces nuclear translocation of p50-containing dimers and that p50 interacts with C/EBPbeta activated by both IL-6 and IL-1beta to induce CRP expression.

3' Untranslated Regions↗
PubMed1997

The sphingomyelin-ceramide pathway participates in cytokine regulation of C-reactive protein and serum amyloid A, but not alpha-fibrinogen.

Maximal induction of the acute-phase proteins C-reactive protein (CRP) and serum amyloid A (SAA) in the human hepatoma cell line Hep3B requires the combination of interleukin (IL)-6 and IL-1. In contrast, IL-1 inhibits fibrinogen induction by IL-6. To explore the possible participation of the sphingomyelin-ceramide pathway in the transduction of cytokine effects, the role of this pathway in expression of CRP, SAA and alpha-fibrinogen was investigated. The cell-permeable ceramide analogues C2 and C6 each greatly potentiated induction of both CRP and SAA mRNA by IL-6+IL-1beta but did not affect the responses of alpha-fibrinogen to IL-6 or to IL-6+IL-1beta. The combination of IL-6+IL-1beta led to increased turnover of sphingomyelin in Hep3B cells. D609, an inhibitor of ceramide production by acidic but not neutral sphingomyelinases, substantially inhibited induction of CRP and SAA by IL-6+IL-1beta. The ability of C2 and C6 to potentiate the effects of cytokines suggests that the sphingomyelin-ceramide pathway participates in induction of CRP and SAA by IL-6+IL-1beta under these experimental conditions, most likely by transducing the effects of IL-1beta. C2 and C6 were unable to substitute for IL-1beta in enhancing IL-6 effects on CRP and SAA, consistent with other reports indicating that the sphingomyelin-ceramide pathway is only a single component of multiple necessary converging pathways for induction of many genes. In contrast, this pathway does not appear to participate in mediating the inhibitory effects of IL-1beta on fibrinogen induction by IL-6.

Apolipoproteins↗
PubMed1997

Chronic inflammation in older people: recognition, consequences, and potential intervention.

In elderly individuals, some chronic inflammatory diseases appear to occur with increased frequency, and recent evidence suggests that some very common chronic, age-related disorders may be propagated and perpetuated by inflammatory processes, perhaps giving rise to the abnormal acute phase protein levels that are seen with increased frequency with aging. The consequences of chronic inflammation in the elderly undoubtedly contribute to excessive morbidity in this population. Treatment of chronic inflammation in the elderly is often difficult, requiring utmost care and close follow-up by a knowledgeable and dedicated physician.

Acute-Phase Proteins↗
PubMed1996

Unstimulated peripheral blood mononuclear cells from patients with the hyper-IgD syndrome produce cytokines capable of potent induction of C-reactive protein and serum amyloid A in Hep3B cells.

The hyper-IgD and periodic fever syndrome (HIDS) and familial Mediterranean fever (FMF) are both characterized by attacks of periodic fever accompanied by acute phase responses that are substantially higher in HIDS than in FMF. To determine whether this difference could be due to differences in production of acute phase protein-inducing mediators, we studied PBMC from HIDS and FMF patients in the inactive phase of disease. Unstimulated PBMC from patients with inactive HIDS released significantly more IL-1 beta, IL-6, and TNF-alpha than did PBMC from patients with FMF, but unstimulated PBMC from the latter group released significantly more IL-1 beta and IL-6 compared with controls. Conditioned medium (CM) derived from PBMC of patients with inactive HIDS induced significantly greater CRP production and significantly higher mRNAs for CRP and SAA in Hep3B cells than did CM derived from the PBMC of patients with inactive FMF. Stimulation of PBMC with LPS led to further increases in cytokine production and in acute phase protein-inducing ability in both patient groups and in controls. These findings suggest that the greater acute phase response seen in HIDS compared with FMF reflects greater production of acute phase protein-inducing cytokines in the former patients and indicates that PBMC from inactive HIDS patients are already activated in vivo. Finally, the finding of both quantitative and qualitative differences in cytokine production by unstimulated PBMC from HIDS and FMF patients supports the likelihood of different pathogeneses of these diseases.

Acute-Phase Proteins↗
PubMed1996

STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6.

Interleukin-6 (IL-6) is the major cytokine inducing transcription of human C-reactive protein (CRP) during the acute phase response. STAT (signal transducers and activators of transcription) family members, recently shown to be important mediators of the effects of many cytokines including IL-6, generally induce their effects by binding to palindromic sequences with TT(N)5AA motifs. We report an IL-6 responsive element in the proximal region of the human CRP 5'-flanking region that bears a TT(N)4AA motif, which we have termed CRP acute phase response element (CRP-APRE). In Hep3B cells, IL-6 but not interferon-gamma was capable of activating CAT constructs driven by the CRP promoter containing CRP-APRE. Overexpressed STAT3 was able to transactivate CRP-chloramphenicol acetyltransferase constructs through the CRP-APRE and was able to enhance endogenous CRP mRNA accumulation in response to IL-6. STAT3 (or an antigenically related molecule) bound to the CRP-APRE in response to IL-6. Overexpression of STAT3 in the presence of IL-6 was capable of inducing expression of a construct consisting of the CRP-APRE and a minimal thymidine kinase promoter lacking a C/EBP site. Taken together, these findings indicate that STAT3 participates in the transcriptional activation of CRP in response to IL-6.

Acute-Phase Proteins↗
PubMed1996

C-reactive protein and serum amyloid A mRNA stability following induction by cytokines.

We determined the effects of cytokine withdrawal on C-reactive protein (CRP) and serum amyloid A (SAA) mRNA abundance in Hep3B cells following 24 h of preinduction with interleukin 6 plus interleukin 1 beta. After cytokine withdrawal, CRP transcription rate rapidly fell to undetectable levels and mRNA levels fell with a half-disappearance time of about 2.5 h. In view of the relatively small amount of CRP transcription occurring at this time, it is likely that this value closely reflects the actual half-life of CRP mRNA. In contrast, substantial SAA transcription continued for at least 8 h, while SAA mRNA fell with a half-disappearance time of about 8.5 h. It is not possible, under these conditions, to determine SAA mRNA half-life, but it clearly was no greater than 8.5 h. Both Actinomycin D (ActD) and cycloheximide enhanced the stability of SAA mRNA, strongly suggesting that SAA mRNA degradation requires synthesis of a short-lived protein. CRP mRNA stability was also enhanced by ActD, but cycloheximide did not have a protracted stabilizing effect, suggesting complex regulatory processes. These studies provide insight into the stability of CRP and SAA mRNA following induction with [IL-6 + IL-1 beta] and into the mechanisms regulating their degradation.

Blotting, Northern↗
PubMed1996

Quantitative and qualitative alterations of acute-phase proteins in healthy elderly persons.

To assess acute-phase proteins in relation to ageing, we measured serum concentrations of C-reactive protein of AGP in 131 healthy elderly individuals (aged >/= 65 years) living independently in the community, and 47 healthy younger individuals. Concentrations of CRP in the older persons (median = 3.0 microg/ml) were significantly greater than in the younger group (median = 0.9 microg/ml, p = 0. 0003). Concentrations of SAA and AGP were similar in the two groups, but AGP glycosylation forms with reduced binding affinity for concanavalin-A (changes that have been observed in chronic inflammatory states) were increased in the elderly sample (p<0.0001). These findings suggest that both quantitative and qualitative alterations of acute-phase proteins occur with physiological ageing in humans.

Activities of Daily Living↗
PubMed1995

The effect of interleukin-1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level.

The combination of interleukin 6 (IL-6) and interleukin 1 (IL-1) synergistically induces the human acute-phase reactant, C-reactive protein (CRP) in Hep3B cells. While previous studies have indicated that IL-6 induces transcription of CRP, the mode of action of IL-1 has not been clearly defined. It has been suggested that the effect of IL-1 might be post-transcriptional, exerted through the 5'-untranslated region (5'-UTR). To evaluate the role of IL-1 in CRP gene expression, we studied the effects of interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) on both the endogenous CRP gene and on transfected CRP-CAT constructs in Hep3B cells. In kinetic studies of the endogenous CRP gene, IL-1 beta alone had no effect on CRP mRNA levels, but when added to IL-6, synergistically enhanced both CRP mRNA levels and transcription, as determined by Northern-blot analyses and nuclear run-on studies. IL-6 alone and the combination of [IL-1 beta + IL-6] each induced increases in mRNA levels roughly comparable with observed increases in transcription. These findings indicate that the effect of IL-1 beta on CRP expression is exerted largely at the transcriptional level in this system. This conclusion was confirmed by studies in Hep3B cells transiently transfected with CRP-CAT constructs, each containing 157 bp of the CRP 5'-flanking region but differing in the length of the 5'-UTR from 104 bp to 3 bp. All constructs responded in the same way; IL-6, but not IL-1 beta, induced significant chloramphenicol acetyltransferase (CAT) expression which was synergistically enhanced 2- to 3-fold by IL-1 beta. These results indicate that IL-1 beta stimulates transcriptional events in the presence of IL-6 and that the upstream 157 bases of the CRP promoter contain elements capable of both IL-6 induction and the synergistic effect of IL-1 beta on transcription.

C-Reactive Protein↗
PubMed1995

Induction of human serum amyloid A in Hep 3B cells by IL-6 and IL-1 beta involves both transcriptional and post-transcriptional mechanisms.

Previous studies of murine serum amyloid A (SAA) regulation during inflammatory states or following exposure to macrophage-conditioned medium have raised the possibility that both post-transcriptional and transcriptional mechanisms participate in induction of this family of proteins. Since IL-6 and IL-1 have been shown to induce SAA in human hepatoma cell lines, we explored the possibility that these cytokines might induce human SAA through post-transcriptional as well as transcriptional mechanisms. In kinetic studies, we found that continuous exposure of Hep 3B cells to either IL-6 or IL-1 beta alone caused only minimal increases in SAA mRNA and marginal increases in transcription (as measured by nuclear runon). In contrast, the combination of these cytokines led to a 23-fold increase in transcription, maximal at 12 h, with continuing increase in mRNA, achieving levels more than 1,000-fold greater than baseline by 72 h. This massive disparity between increases in mRNA and in transcription rate strongly supports the participation of post-transcriptional mechanisms in SAA induction by (IL-6 + IL-1 beta), whereas the lag between peaks of transcription and mRNA abundance reflects a relatively slow degradation rate of SAA mRNA. As observed by other workers, mean size of SAA mRNA decreased progressively over the course of incubation. Simultaneous kinetic studies of complement factors B and C3, haptoglobin, and alpha-1 protease inhibitor revealed several different patterns of response to IL-6 and IL-1 beta.

Blotting, Northern↗