Including Interleukin-6 Levels Research Articles

Inflammation related to synovectomy during total knee replacement in patients with primary osteoarthritis

We compared inflammation in the knee after total knee replacement (TKR) for primary osteoarthritis between two groups of patients undergoing joint replacement with and without synovectomy. A total of 67 patients who underwent unilateral TKR were randomly divided into group I, TKR without synovectomy, and group II, TKR with synovectomy. Clinical outcomes, serial serum inflammatory markers (including interleukin-6 (IL-6), CRP and ESR) and the difference in temperature of the skin of the knee, compared with the contralateral side, were sequentially evaluated until 26 weeks after surgery. Pre-operatively, there were no statistically different clinical parameters between groups I and II. At the 26-week follow-up, both groups had a similarly significantly improved American Knee Society clinical score (p < 0.001) and functional score (p < 0.001) with no differences between the groups. Similar changes in serial inflammatory markers were found in both groups, including mean peak levels of IL-6 (189 pg/ml (SD 53.4) versus 201 pg/ml (SD 49.4) for groups I and II, respectively) and CRP (91 mg/L (SD 24.1) versus 88 mg/L (SD 23.4), respectively) on the first post-operative day, returning to pre-operative values at two and six weeks, respectively. The mean peak level of ESR for the respective two groups was 46 mm/hr versus 48 mm/hr at two weeks, which had still not returned to its pre-operative mean value at 26 weeks. The elevation in the skin temperature appeared to mirror the peak elevation of the ESR, with a range of 2.5° C to 4.5° C with some reduction at 26 weeks but still exceeding the pre-operative value. We concluded that synovectomy at the time of TKR does not provide any benefit to the clinical outcome or shorten the duration of the inflammatory response after surgery.

Differential effects of Radix Paeoniae Rubra (Chishao) on cytokine and chemokine expression inducible by mycobacteria

BackgroundUpon initial infection with mycobacteria, macrophages secrete multiple cytokines and chemokines, including interleukin-6 (IL-6), IL-8 and tumor necrosis factor-α (TNF-α), to mediate host immune responses against the pathogen. Mycobacteria also induce the production of IL-10 via PKR activation in primary human monocytes and macrophages. As an anti-inflammatory cytokine, over-expression of IL-10 may contribute to mycobacterial evasion of the host immunity. Radix Paeoniae Rubra (RPR, Chishao), a Chinese medicinal herb with potentials of anti-inflammatory, hepatoprotective and neuroprotective effects, is used to treat tuberculosis. This study investigates the immunoregulatory effects of RPR on primary human blood macrophages (PBMac) during mycobacterial infection.MethodsThe interaction of Bacillus Calmette-Guerin (BCG) with PBMac was used as an experimental model. A series of procedures involving solvent extraction and fractionation were used to isolate bioactive constituents in RPR. RPR-EA-S1, a fraction with potent immunoregulatory effects was obtained with a bioactivity guided fractionation scheme. PBMac were treated with crude RPR extracts or RPR-EA-S1 before BCG stimulation. The expression levels of IL-6, IL-8, IL-10 and TNF-α were measured by qPCR and ELISA. Western blotting was used to determine the effects of RPR-EA-S1 on signaling kinases and transcriptional factors in the BCG-activated PBMac.ResultsIn BCG-stimulated macrophages, crude RPR extracts and fraction RPR-EA-S1 specifically inhibited IL-10 production while enhanced IL-8 expression at both mRNA and protein levels without affecting the expressions of IL-6 and TNF-α. Inhibition of BCG-induced IL-10 expression by RPR-EA-S1 occurred in a dose- and time-dependent manner. RPR-EA-S1 did not affect the phosphorylation of cellular protein kinases including MAPK, Akt and GSK3β. Instead, it suppressed the degradation of IκBα in the cytoplasm and inhibited the translocation of transcription factor NF-κB1 p50 to the nucleus.ConclusionRPR crude extracts and its fraction RPR-EA-S1 inhibited anti-inflammatory cytokine IL-10 and enhanced pro-inflammatory chemokine IL-8 expression in BCG-activated PBMac. The inhibitory effects of RPR-EA-S1 on IL-10 expression in BCG-activated PBMac may be due to the reduced nuclear translocation of NF-κB1 p50.

Treatment of the Infected Total Shoulder Arthroplasty With Antibiotic-Impregnated Cement Spacers

Deep infections of the shoulder, including primary shoulder sepsis and infection after shoulder arthroplasty, are rare but devastating problems. Treatment of the infected shoulder has proven to be difficult with a high rate of complications. Few reports have been able to effectively eradicate infection while preserving anatomy and function of the shoulder. The purpose of the present article is to report our experience in treating the infected shoulder arthroplasty and shoulder sepsis with the use of 2 types of antibiotic-impregnated cement spacers. We treated 30 patients (ages 45-89 years) with either primary shoulder sepsis with humeral head osteomyelitis or chronic infection of a shoulder arthroplasty with extensive debridement, removal of the implant or humeral head, placement of an antibiotic spacer, and intravenous antibiotics. Fourteen of those shoulders were treated with an intraoperatively crafted antibiotic-impregnated cement spacer, and 16 shoulders were treated with a commercially produced antibiotic-impregnated spacer. Clinical as well as laboratory data, including interleukin-6 levels, were followed postoperatively to determine the most appropriate time for reimplantation. Among the 30 infected shoulders treated, we observed no recurrence of infection, and all patients had improved pain and function, as well as subjective and objective shoulder evaluation scores. Treatment with a spacer aids in maintaining the soft-tissue envelope, prevents severe scarring, and helps maintain some function of the shoulder once reconstruction is performed. Also, serum interleukin-6 level appears to be useful in the evaluation of shoulder infection for determination of appropriate timing for revision.

Angiogenic Molecules and Inflammatory Cytokines in Patients with Thalassemia Major and Double Heterozygous HbS/Beta-Thalassemia; the impact of Deferasirox.

Abstract 2018Poster Board I-1040Angiogenesis is a crucial process in the pathogenesis of several inflammatory, autoimmune and malignant diseases. Endothelial damage and inflammation make a significant contribution to the pathophysiology of sickle cell disease (SCD) and the beta-thalassemia syndromes. However, there are very limited data in the literature for the role of angiogenic cytokines in the pathogenesis of thalassemia major (TM) and of double heterozygocity of SCD and beta-thalassemia (HbS/beta-thal). Deferasirox (Exjade®) is a once-daily orally administered iron chelator approved for the treatment of transfusional iron overload in patients with transfusion-dependent anemia which seems to reduce markers of inflammation in TM. The aim of this prospective study was to evaluate the levels of angiogenic and inflammatory cytokines in patients with TM and HbS/beta-thal with iron overload who received chelation therapy with deferasirox. Forty-five patients (16M/29F) with TM and 20 patients (7M/13F) with HbS/beta-thal were evaluated. Deferasirox was administered at a dose between 10-30 mg/kg/day based on the number of blood transfusions received before the initiation of treatment. After 3 months, dose adjustments (increases) were allowed in increments of 5 mg/kg/day every 3 months as required to reduce markers of iron overload. Deferasirox was given for a period of 12 months. Serum levels of angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin (Ang), angiopoietin (Angp)-1 and -2 and of inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-á), IL-1á, IL-1β, IL-4, IL-10 and transforming growth factor (TGF)-β1 and β2, were measured at baseline (day 1 of deferasirox administration) and then after 12 months post-deferasirox therapy, using ELISA methodology (R&D Systems, Minneapolis, MN, USA, for angiogenin cytokines and ILs and Diaclone, Bensancon, France for TNF-á, TGF-β1 and TGF-β2). Twenty healthy blood donors of similar age and gender were also evaluated as control group. Standard hematology and biochemistry was evaluated monthly in all patients. Patients with both TM and HbS/beta-thal had increased levels of all studied angiogenic cytokines compared with healthy controls but reduced levels of Angp-1/Angp-2 ratio (p<0.01 for all comparisons). Patients with HbS/beta-thal had increased levels of Angp-2 (p=0.002) and reduced levels of Angp-1/Angp-2 ratio (p<0.001) compared to TM patients. Both TM and HbS/beta-thal patients had also increased levels of IL-6 (p=0.008), IL-1á (p=0.01), TGF-β2 (p=0.01), IL-10 (p=0.02), IL-4 (p=0.03), and TNF-á (p=0.01) compared to controls. There were no differences between TM and HbS/beta-thal patients in terms of inflammatory cytokines. In TM patients, VEGF strongly correlated with TGF-β1 (r=0.652, p<0.001), platelet count (r=0.503, p=0.001) and white blood cell (WBC) count (r=0.484, p=0.002), while Angp-2 strongly correlated with TNF-á (r=0.536, p=0.001), WBC count (r=0.430, p=0.008) and platelet count (r=0.330, p=0.01). In HbS/beta-thal patients Angp-1/Angp-2 ratio strongly correlated with ALT (r=-0.611, p=0.007) and Hb (r=0.498, p=0.036). Twelve months post-deferasirox administration, there was a dramatic reduction of ferritin, SGOT and SGPT compared with baseline values in both patient groups (p<0.0001). TM patients showed a continuous increase of both VEGF (mean±SD: from 680±489 ng/ml prior to deferasirox to 801±547 ng/ml post-deferasirox; p=0.002) and bFGF (from 16.2±17.1 ng/ml prior to deferasirox to 33.1±28.8 ng/ml post-deferasirox; p=0.001) after 12 months of deferasirox therapy. No other changes were observed in TM group regarding angiogenic molecules. Patients of HbS/beta-thal showed no alterations in terms of angiogenic cytokines that continued to be elevated compared to controls. In terms of inflammatory cytokines deferasirox produced a reduction of TNF-á in both studied groups (p<0.01 for all comparisons). Our study suggests that angiogenic and inflammatory cytokines are increased in patients with TM and HbS/beta-thal and thus they have a role in the pathogenesis of these disorders. Angiopoietins seem to be strongly implicated in the biology mainly of HbS/beta-thal. However, further studies are needed to fully elucidate this role as well as the effect of deferasirox, if any, on inflammation. Deferasirox seems to have no impact on angiogenic cytokines. Disclosures:No relevant conflicts of interest to declare.

Interleukin‐6 and type I interferon–regulated genes and chemokines mark disease activity in dermatomyositis

Up-regulation of whole blood type I interferon (IFN)-driven transcripts and chemokines has been described in a number of autoimmune diseases. An IFN gene expression "signature" is a candidate biomarker in patients with dermatomyositis (DM). This study was performed to evaluate the capacity of IFN-dependent peripheral blood gene and chemokine signatures and levels of proinflammatory cytokines to serve as biomarkers for disease activity in adult and juvenile DM. Peripheral blood samples and clinical data were obtained from 56 patients with adult or juvenile DM. The type I IFN gene signature in the whole blood of patients with DM was defined by determining the expression levels of 3 IFN-regulated genes (IFIT1, G1P2, and IRF7) using quantitative real-time reverse transcription-polymerase chain reaction. Multiplexed immunoassays were used to quantify the serum levels of 4 type I IFN-regulated chemokines (IFN-inducible T cell alpha chemoattractant, IFNgamma-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], and MCP-2) and the serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). DM disease activity correlated significantly with the type I IFN gene signature (r = 0.41, P = 0.007) and with the type I IFN chemokine signature (r = 0.61, P < 0.0001). Furthermore, the serum levels of IL-6 were significantly correlated with disease activity (r = 0.45, P = 0.001). In addition, correlations between the serum levels of IL-6 and both the type I IFN gene signature (r = 0.47, P < 0.01) and the type I IFN chemokine signature (r = 0.71, P < 0.0001) were detected in patients with DM. These results suggest that serum IL-6 production and the type I IFN gene signature are candidate biomarkers for disease activity in adult and juvenile DM. Coregulation of the expression of IFN-driven chemokines and IL-6 suggests a novel pathogenic linkage in DM.

Study of adventitial inflammation and inflammatory factors in pathogenesis of allograft arteriosclerosis in rats

To study the roles of serum inflammatory factors IL-6 and TNF-alpha and allograft adventitial inflammation in the pathogenesis of allograft arteriosclerosis in rats. Thirty-six allogeneic allograft rats and 16 syngeneic allograft rats were randomly divided into 4 groups (9 rats in each experimental group and 4 in each control group): A, harvested at Week 1 post-operation; B, harvested at Week 2 post-operation; C, harvested at Week 3 post-operation; D, harvested at Week 4 post-operation. Blood samples were collected before transplantation and after harvest. The method of ELISA was used for testing serum inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor-alpha(TNF-alpha), HE staining for pathologic changes of aortic allograft and immunohistochemical method for expression of alpha-actin, cyclin dependent kinase-1 (CDK(1)) and proliferating cell nuclear antigen (PCNA). Compare the inflammatory factors and other observations between groups and preoperative. At Week 1 post-operation, a large amount of inflammatory cell infiltration in adventitia was observed; at Week 2 post-operation, slight collagen fibers hyperplasia with inflammatory infiltration; at Week 4 post-operation, obvious adventitia thickening with a large number of smooth muscle cells, collagen fibers and inflammatory cells, smooth muscle cells migration from adventitia to intima. Expressions of alpha-actin, CDK(1) and PCNA kept increasing with time in adventitia (P < 0.05). There was a significant increase in serum TNF-alpha level in Groups A, B, C and D, as compared with pre-operative basal level (P < 0.01). There was no difference between controls and pre-operative basal level. IL-6 level slightly declined in the middle stage, but finally increased in experimental group B (P < 0.05) while it significantly increased in Groups A, C, D (P < 0.01). In the control groups A, B, C, it was higher than pre-operative level (P < 0.05). In experimental groups A, C, D, it had a significant increase as compared with controls (P < 0.01). In abdominal aortic allograft models, obvious angiosclerosis was found in adventitia and intima in accordance with the severity of adventitial inflammation. Thus the inflammatory factors and inflammatory cell infiltration in adventitia are both involved in the pathogenesis of early allograft arteriosclerosis.

Protein biochip array technology to monitor rituximab in rheumatoid arthritis

In rheumatoid arthritis (RA) there are currently no good indicators to predict a clinical response to rituximab. The purpose of this study was to monitor and determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to rituximab in RA. Blood samples were collected at baseline and at 3 months from 46 RA patients who were treated with rituximab. Responders are defined by the presence of three of four American College of Rheumatology criteria: >or=20% decrease in C-reactive protein, visual analogical score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28) (four values) by >or=1.2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array, including interleukin-6 (IL-6), tumour necrosis factor-alpha, IL-1a, IL-1b, IL-2, IL-8, interferon-gamma, IL-4, IL-10, monocyte chemoattractant protein-1, epidermal growth factor and vascular growth factor. We showed that C-reactive protein and IL-6 levels decrease significantly at 3 months in the responder group compared with baseline. At day 90 we identified a cytokine profile which differentiates responders and non-responders. High serum levels of two proinflammatory cytokines, monocyte chemoattractant protein-1 and epidermal growth factor, were significantly higher in the responder group at day 90 compared with non-responders. However, we were not able to identify a baseline cytokine profile predictive of a good response at 3 months. These findings suggest that cytokine profiling by proteomic analysis may be a promising tool for monitoring rituximab and may help in the future to identify responder RA patients.

Deferasirox Reduces Serum TNF-α but Impairs Renal Function in Patients with Thalassemia Major after 12 Months of Therapy

Deferasirox is an oral iron chelator approved for the management of iron overload in thalassemia major (TM). However, there are some concerns for its effect on renal function. Cystatin C (Cys-C) is a cysteine protease inhibitor, which is considered as a sensitive marker of GFR. Inflammation process has been recently implicated in TM pathophysiology. The aim of this study was to evaluate the effect of deferasirox on renal function and inflammatory cytokines in 52 TM patients. Deferasirox was administered at a dose between 10–30 mg/kg/day for a 12-month period. Serum Cys-C, serum creatinine (Cr), clearance of Cr (Ccr), albuminuria and inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1β, IL-4, IL-10 and transforming growth factor (TGF)-β1 and β2, were measured at baseline and then after 6 and 12 months post-deferasirox therapy. Standard hematology and biochemistry was evaluated monthly. Serum Cys-C was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring, Liederbach, Germany). Serum levels of the above cytokines were determined using ELISA (R&D Systems, Minneapolis, MN, USA, for ILs, and Diaclone, Bensancon, France for TNF-α, TGF-β1 and TGF-β2). Ten healthy blood donors were also evaluated as control group. At baseline, TM patients had elevated values of Cys-C (p<0.0001) compared with controls. Specifically, 21/52 patients (40%) had higher Cys-C values than the upper normal limit according to manufacturer (0.95 mg/L), while no patient had increased levels of serum Cr (>1.4 mg/dl) and only 6 (11.5%) had low Ccr (<80 ml/min). Before deferasirox administration, TM patients had also increased levels of IL-6 (p=0.008), IL-1α (p=0.015), TGF-β2 (p=0.017), IL-10 (0.021), IL-4 (p=0.039), and a borderline increase of TNF-α (p=0.05) compared with controls (Table). Serum levels of Cys-C correlated strongly with Cr (r=0.657, p<0.0001), and Ccr (r=−0.625, p<0.0001) but also with IL-6 (r=0.441, r<0.001) and proteinuria (r=0.261, p=0.037). Il-1a correlated with Hb (r=−0.417, p<0.001) and IL-4 (r=0.474, p<0.001), while IL-6 correlated with TNF-α (r=0.37, p<0.01). After 6 and 12 months of therapy, deferasirox produced a dramatic reduction of ferritin, SGOT and SGPT compared with baseline values (p<0.0001), but concomitantly we observed an increase of Cys-C and Ccr during the same period (p<0.0001). In particular at the end of the study 32/52 patients (61.5%) had increased Cys-C values, while 10 (19.2%) had low Ccr and only one high serum Cr. Interestingly serum levels of TNF-α reduced post-deferasirox administration (p=0.01), while the levels of all other cytokines remained unchanged during therapy (Table). Our study suggests that deferasirox is an effective chelator in TM. However, its effect on renal function is not insignificant and needs further investigation. Inflammatory cytokines seem to have a role in the pathogenesis of TM but further studies are needed to fully elucidate this role as well as the effect of deferasirox, if any, on inflammation.Table 1. Characteristics of patients & controls (mean values ± SD)ParametersControls (n=10)Patients-baseline values (n=52)p-value (patientsvs.controls)Patients-12-month valuesp-value patients (baselinevs.12 m)Age(years)40.8±11.739.5±10.90.782Gender(Male/Female)4/622/300.346Hb(g/dL)14.8±2.68.8±1.4<0.00018.7±1.5AST(U/L)29.3±10.146.7±23.9<0.000135.5±19.2<0.0001ALT(U/L)23.8±12.550.7±28.6<0.000134.3±22.1<0.0001Ferritin(μg/L)88±34.22355±1380<0.00011516±1320<0.0001Serum Creatinine (mg/dL)0.8±0.10.7±0.10.8230.8±0.20.001Creatinine Clearance (ml/min/1.732)125.2±22.7126.5±29.90.227117.0±31.10.005Proteinuria(mg/24h)55.4±28.2322.9±461.6<0.0001323.4±417.00.976Cystatin-C (mg/L)0.76±0.110.93±0.26<0.00011.12±0.37<0.0001Inflammatory CytokinesIL-1α (pg/mL)0.08±0.190.65±0.800.0151.06±1.130.114IL-1β (pg/mL)2.30±2.541.68±2.370.4752.05±2.820.571IL-4 (pg/mL)ND0.78±1.830.0390.28±0.590.167IL-6 (pg/mL)0.09±0.212.50±4.420.0083.00±7.510.752TNF-α (pg/mL)1.13±2.053.85±7.480.050.46±1.400.015TGF-β1 (ng/mL)87.1±21.7107.5±53.60.180112.1±74.00.678TGF-β2 (pg/mL)5.62±10.519.5±26.40.01715.8±29.70.318

Visual prognosis and vitreous cytokine levels after arteriovenous sheathotomy in branch retinal vein occlusion associated with macular oedema

To investigate the relationship between vitreous levels of cytokines, including interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), and visual prognosis after pars plana vitrectomy (PPV) with arteriovenous sheathotomy in patients with branch retinal vein occlusion (BRVO) associated with macular oedema. We studied 60 patients with logMAR visual acuity (VA) scores of < 0.3 and visual impairment secondary to BRVO-associated macular oedema. All patients underwent PPV with arteriovenous sheathotomy. At the time of PPV, vitreous samples were collected from the operated eye and vitreous levels of VEGF and IL-6 were measured. Best corrected VA (BCVA) (using a logMAR chart) and foveal thickness (FT) (using optical coherence tomography) were monitored for up to 6 months after PPV. Both BCVA and FT significantly improved after PPV. According to multiple regression analysis, both the improvement in BCVA and decrease in FT were closely related to the vitreous level of IL-6 but not to that of VEGF. The vitreous level of VEGF was strongly correlated with duration of BRVO. Both improvement in BCVA and decrease in FT were observed after PPV in BRVO patients with macular oedema. Interestingly, these visual prognoses strongly correlate with the vitreous level of IL-6, whereas the duration of BRVO strongly correlates with the vitreous level of VEGF.

Inflammation and Rate of Cognitive Change in High-Functioning Older Adults

Inflammatory proteins including interleukin-6 (IL-6) and C-reactive protein (CRP) have been associated with incident cognitive impairment, but little research has addressed their effects on the rate of cognitive change, and findings are mixed. The purpose of this study was to examine the relationship between serum levels of IL-6 and CRP and the rate of cognitive change across a range of cognitive domains in a sample of healthy older persons. Growth curve analysis was performed on data from the MacArthur Study of Successful Aging, a longitudinal cohort study of high-functioning older adults aged 70-79 years at baseline in 1988 and reinterviewed in 1991 and 1995 (N = 851). Individual growth curve parameters were derived from baseline and follow-up performance in abstraction, language, spatial ability, verbal recall, spatial recognition, and global cognitive function based on age, IL-6, CRP, and covariates. Cross-sectionally, there is a generally linear negative relationship between inflammation and cognition, such that higher levels of inflammation are associated with lower levels of baseline cognitive function. After controlling for potential confounders, there was no effect of inflammation on baseline cognitive function or the rate of longitudinal cognitive change. However, persons in the top tertile on IL-6 were at an increased risk of incident declines on the Short Portable Mental Status Questionnaire (SPMSQ). Although high levels of inflammation are associated with incident cognitive impairment, these results do not generalize to the full range of cognitive changes, where the role of inflammation appears to be marginal.

The role of cytokines in inflammatory response after total knee arthroplasty in patients with rheumatoid arthritis

Surgery and trauma is accompanied by changes in blood levels of certain cytokines and chemokines including interleukin-6 (IL-6) and interleukin-8 (IL-8). However, there is little data on correlations between local and systemic levels of these mediators during orthopedic surgeries in rheumatoid arthritis (RA) patients who already show increased levels of proinflammatory cytokines due to their disease. We aimed to measure dynamics of blood and drainage fluid levels of IL-6 and IL-8 in postoperative period in rheumatoid arthritis patients undergoing knee replacement surgery and correlate these changes with blood levels of C-reactive protein (CRP), body temperature and pain. We report that blood and drainage fluid levels of IL-6 and IL-8 showed significantly increasing trend during the 36-h period after the surgery. Drainage fluid levels of both cytokines were significantly higher in comparison with blood, indicating their local production in the operated joint. In contrast, levels of CRP were higher in blood than in drainage fluid. Despite the fact that the levels of tested cytokines had already been high in RA patients before surgery, we conclude that after surgery their levels were being much significantly enough high in drainage fluid to reflect dominated local inflammatory reaction to surgical stress and trauma.

Soluble IL-6 Receptor Synergistically Stimulates the Growth of Multiple Myeloma with IL-6 and Confers Resistance to Bortezomib.

Proinflammatory cytokines including Interleukin-6 (IL-6), TNFa, and IL-8, involved in a variety of cellular responses including proliferation, differentiation, and inflammatory processes. They play a pivotal role in the pathogenesis of multiple myeloma (MM). Elevated IL-6 and souble IL-6 receptor (sIL-6R) levels have been found in MM patients indicating that its production is not only coordinated as part of a disease progression but also strongly associated with outcome of anti-cancer therapy. Even though Bortezomib, one of proteosome inhibitors, is known to effectively induce the apoptosis of U266 myeloma cells via caspase-dependent pathway and inactivation of NF-kB, these apoptotic effects by Bortezomib could be decreased in U266 myeloma cells exposed to various proinflammatory cytokines. However, roles of IL-6 and sIL-6R in the progression of MM and response to anti-cancer treatment still remain to be explored. In this study, ELISA assay showed higher levels of IL-6, sIL-6R, and IL-8 in bone marrow plasma of MM patients compared to control group, which is the similar results of other investigators. Bortezomib-induced apoptotic effect in U266 myeloma cells was reduced by treatment of IL-6. This Bortezomib-induced apoptotic effect was more reduced in U266 myeloma cells following combined treatment with IL-6 and sIL-6R, although sIL-6R only did not exert on apoptotic effect. Caspase-3 activity by Bortezomib treatment decreased when U266 cells exposed to combined IL-6 and sIL-6R. In addition, U266 cells treated with combined IL-6 and sIL-6R synergically activated the phosphorylation of STAT-3 and ERK resulting in prolong survival of U266 cells. Phosphorylation of STAT-3 and ERK in U266 myeloma cells following combined treatment of IL-6 and sIL-6R did not affect by Bortexomib treatment. These results suggest that the levels of IL-6 and sIL-6R in bone marrow plasma may strongly be associated with clinical outcome of Bortezomib treatment in MM patients.

Yoga Therapy Improves Markers of Inflammation and Overall Weil-Being in Patients with Chronic Heart Failure

BACKGROUND: Pro-inflammatory markers are associated with unfavorable cardiovascular outcomes in chronic heart failure (CHF). Despite widespread use of effective pharmacological agents, the morbidity of patients with CHF remains high. Yoga therapy (exercise and breathing practices) in CHF may improve the well-being of these patients and retard the pathogenic mechanisms observed in CHF. METHODS: To test the hypothesis that yoga therapy improves quality of life and levels of inflammatory markers in CHF, we followed 12 patients with New York Heart Association Class II or III symptoms of heart failure. Patients were managed on appropriate medical therapy, for at least six months. Half the patients were randomized to the yoga treatment and half were randomized to usual medical care which included a home walk progression. The yoga group attended two 75 minute classes per week for an 8 week period. Measured variables included blood pressure, flexibility, waist/hip ratio, a ramp protocol treadmill test to peak exertion, and serum markers associated with the prognosis of HF, including interleukin-6 (IL-6), C-reactive protein, and extracellular superoxide dismutase (EC-SOD). The Minnesota Living with Heart Failure Questionnaire (MLHF) was also administered. RESULTS: Statistical analysis (SPSS-12, Non-parametric Mann-Whitney U-Test) found that levels of IL-6 and EC-SOD decreased significantly in the yoga intervention (p<0.001 and p<0.02, respectively), but not in the control group. The MLHF scores decreased by one standard deviation in five of the yoga treatment patients (n=6) after completion of the study. All yoga group participants tolerated the yoga intervention without complication and reported an improved ability to perform activities of daily living. This was congruent with the significant improvement in treadmill test time to peak exertion (p=.028) found in the treatment group. CONCLUSIONS: Yoga therapy appears safe to implement and improves quality of life in patients with chronic heart failure. Furthermore, it may provide a beneficial cardiovascular response to exercise and improves levels of inflammatory markers associated with adverse cardiovascular events.

Effects of Salvia miltiorrhiza on serum levels of inflammatory cytokines in patients with severe acute pancreatitis

To study the effects of Salvia miltiorrhiza on serum levels of cytokines including interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) in patients with severe acute pancreatitis (SAP). Thirty-six SAP patients were randomly divided into Salvia miltiorrhiza-treated group and non-Salvia miltiorrhiza-treated group with eighteen patients in each group. Fourteen age-matched healthy volunteers were assigned to control group. Serum levels of IL-6, IL-8, and TNF-alpha were tested within 24 hours of admission and 7 days after admission. Compared with those of the healthy volunteers, serum levels of the three cytokines of the SAP patients were significantly elevated (P<0.05). Serum levels of the three cytokines were significantly decreased in both Salvia miltiorrhiza-treated group and non-Salvia miltiorrhiza-treated group after 7-day treatment (P<0.05). The declining of the serum levels of the three cytokines in Salvia miltiorrhiza-treated group was more obvious than that in non-Salvia miltiorrhiza-treated group. Salvia miltiorrhiza can treat SAP patients by reducing the serum levels of IL-6, IL-8, and TNF-alpha.

Polymorphisms in the interleukin 6 and transforming growth factor β1 gene and risk of dementia: The Rotterdam Study

Inflammatory mechanisms are involved in the pathogenesis of dementia. Inflammatory cytokines, including interleukin-6 (IL-6) and transforming growth factor β1 (TGFβ1), have been found in association with Alzheimer pathology and there is evidence for direct involvement of these cytokines in formation of amyloid plaques. Polymorphisms in genes encoding for IL-6 and TGFβ1 are associated with plasma levels of IL-6 and TGFβ1. Studies examining the association between polymorphisms in these genes and dementia yielded conflicting results. The purpose of this study was to examine the association between genetic variance in IL-6 and TGFβ1 and risk of dementia. We examined this association in the Rotterdam Study, a prospective population-based cohort study in the elderly. Polymorphisms in the IL-6 (−174G>C) and TGFβ1 gene (−800G>A, −509C>T, +10T>C, +25G>C and 263C>T) were genotyped and haplotypes of the TGFβ1 gene were constructed. In a random subset IL-6 plasma levels were measured. During follow-up (mean 9.2 years), 743 dementia cases were identified. We estimated the association between individual polymorphisms and haplotypes with dementia with Cox’ proportional hazard models. No association was found between the −174G>C polymorphism in the IL-6 gene and risk of dementia. No association was found between polymorphisms and constructed haplotypes in the TGFβ1 gene and risk of dementia or Alzheimer's disease. No association was found between IL-6 genotype and IL-6 plasma levels in the random subset. Associations did not differ across APOE genotypes. Our findings do not suggest involvement of genetic variance in IL-6 and TGFβ1 in the development of dementia.

Diagnostic and predictive value of CSF d-ROM level in influenza virus-associated encephalopathy

The aim of this study was to assess the validity of serum and CSF oxidative status of patients with IE in their initial stage through the d-ROM (Diacron-Reactive Oxygen Metabolites, Italy) test, compared to those with other neurological diseases. The study was conducted on the following four groups: (1) influenza virus-associated encephalopathy (IE, n = 8), including four patients showing neurological sequelae or mortal; (2) influenza virus-associated febrile seizures (IFS, n = 11); (3) febrile convulsion (FC, n = 10): (4) enterovirus-associated encephalopathy (EE, n = 4), including one patient with neurological sequelae. The CSF d-ROM levels in the IE group were significantly higher than those in the IFS and the FC groups but not in the EE group. In addition, general laboratory findings such as leukocytes, platelets, C-reactive protein, aspartate aminotransferase, creatinine, creatinine kinase and LDH, including interleukin-6 (IL-6), were analyzed in each group. The CSF d-ROM levels in the IE group were significantly higher than those in the IFS and FC groups but not in the EE group. As for the serum d-ROM levels and general laboratory findings, with the exception of CSF IL-6 levels in IE, no significant differences were detected compared with the other groups. In patients with IE, the CSF d-ROM levels could be a valid predictive biomarker of the severity, and oxidative stress may be related to the pathogenesis of IE.

Body Fat Mass and Serum Leptin Levels Influence Epoetin Sensitivity in Patients With ESRD

Dose requirements of epoetin vary considerably among patients with end-stage renal disease (ESRD), whereas determinants of epoetin sensitivity are poorly understood. Fat mass is an important source of adipokines, including interleukin 6 (IL-6), which is associated with decreased epoetin sensitivity. Furthermore, the adipokine leptin stimulates human erythroid development in vitro. In the present study, we investigate the impact of fat mass and leptin level on epoetin sensitivity in patients with ESRD. One hundred sixty-six patients with ESRD (107 men; 64%) with a mean age of 56.9 +/- 0.9 years were studied in a post hoc cross-sectional analysis. Body composition was analyzed by dual-energy X-ray absorptiometry and correlated with serum markers of inflammation and leptin (analyzed by enzyme-linked immunosorbent assays), as well as with epoetin dose, in international units administered per week (IU/wk). To correct for differences in body mass and hemoglobin (Hb) levels, epoetin sensitivity was approximated as epoetin/Hb ratio, ie, epoetin dose per unit of Hb (IU/wk/g/dL) and epoetin/Hb/kg ratio, ie, epoetin dose per unit of Hb and kilogram of patient body weight (IU/wk/Hb/kg). Patients were divided into 3 groups according to epoetin/Hb/kg ratio (no-epoetin group, low-epoetin group, and high-epoetin group). The 3 groups had significantly different serum levels of high-sensitivity C-reactive protein (hsCRP; median, 8.6 versus 3.1 and 8.0 mg/L, respectively; P < 0.05), neopterin (median, 112.4 versus 94.3 and 96.1 ng/L, respectively; P < 0.05), and IL-6 (median, 6.8 versus 4.1 and 6.5 ng/mL, respectively; P < 0.05). Significant between-group differences also were found in fat mass and leptin levels (median, 14.8 versus 10.5 and 7.9 ng/mL, respectively; P = 0.02). In univariate analyses, significant relationships between epoetin sensitivity indices, leptin levels, and levels of the inflammatory markers hsCRP and IL-6 were found. In a multivariate stepwise regression model, log ferritin, parathyroid hormone, log leptin, log IL-6, and polycystic kidney disease were significantly associated with the epoetin/Hb ratio. The present study shows that leptin level may be a predictor of epoetin sensitivity. The effect could be either direct stimulation of erythropoiesis or indirect stimulation by associated adipokines. Although truncal fat is associated with secretion of proinflammatory cytokines, this secretion appears not to have inhibitory effects on epoetin sensitivity in the presence of high leptin levels.

Interleukin-6 and flow-mediated dilatation as markers of increased vascular inflammation in women receiving hormone therapy

The lack of a beneficial long-term cardiovascular effect of hormone therapy and the early incidence of cardiovascular adverse events observed in recent randomized studies have been related to a heightened inflammatory effect of hormone therapy. We evaluated the effect of different postmenopause therapies on inflammatory markers and endothelial function in 205 postmenopausal women before and after therapy. all postmenopausal women, estrogens alone increased plasma levels of C-reactive protein (CRP) but decreased all other markers of inflammation including interleukin-6 (IL-6) (CRP: +75% +/- 11%, intracellular adhesion molecule: -21% +/- 4%, vascular cell adhesion molecule: -15% +/- 6%, E-selectin: -18% +/- 4%, s-thrombomodulin -10.5% +/- 3.7%, IL-6 -14% +/- 6%; percent changes, P < 0.01 compared with baseline). Raloxifene and tibolone did not significantly affect the overall inflammatory milieu. In a minority of patients, estrogen-progestogen associations and tibolone increased IL-6 levels and induced unfavorable changes on inflammation markers (CRP: +93% +/- 8%, intracellular adhesion molecule: -3% +/- 2%, vascular cell adhesion molecule: -5% +/- 2%, E-selectin: +6% +/- 2%, s-thrombomodulin: +5% +/- 2%, IL-6: +12% +/- 4%; percent changes compared with baseline). Patients with increased IL-6 levels were older and had a longer time since menopause. In all patients except those with increased IL-6 levels, hormone therapy improved endothelial function, whereas tibolone and raloxifene did not significantly change endothelial function compared with baseline. A worsening of endothelial function was detected in patients with increased IL-6 levels during therapy. Postmenopausal hormone therapy is associated with decreased vascular inflammation; however, in patients with a longer time since menopause, postmenopause hormone therapy may increase inflammation and worsen endothelial function. These unfavorable vascular effects may be detected by an elevation in IL-6 levels and by a lack of improvement in endothelial function.

Interleukin-6 Sequence Variants Are not Associated with Prostate Cancer Risk

Interleukin-6 Sequence Variants Are not Associated with Prostate Cancer Risk

Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages.

We investigated the cellular basis for secretion of inflammatory cytokines in mice following intravenous administration of adenoviral vectors (Ad). Serum inflammatory cytokines including interleukin-6 (IL-6), IL-12, and tumor necrosis factor-alpha (TNF-alpha) were detected as early as 6 h following intravenous injection of Ad-expressing Escherichia coli beta-galactosidase (Ad-lacZ). Ad-lacZ readily accumulated in the splenic marginal zone 1 h after intravenous infusion, where both dendritic cells (DCs) and macrophages were transduced and activated within 6 h. Flow cytometric analyses showed that the expression of Ia and CD86 antigens was markedly enhanced on splenic DCs indicating their activation in vivo by Ad-lacZ. Upon ex vivo culture, these early-activated splenic DCs spontaneously produced high levels of IL-6 and IL-12. By contrast, activated splenic macrophages spontaneously secreted only IL-6. Elimination of tissue macrophages and splenic DCs in vivo considerably reduced the early release of IL-12, IL-6, and TNF-alpha and significantly blocked the specific cellular immune response to Ad and the transgene product in vivo. Our findings indicate that preferential activation of DCs and macrophages may account for Ad-triggered acute inflammatory response in vivo in mice. Moreover, DCs and macrophages may play different roles in this process in terms of their abilities to produce distinct patterns of inflammatory cytokines.