Tag: cytokines

Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta

Abstract:

OBJECTIVES: Too vigorous exercise or activity increase frequently triggers postexertional malaise in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a primary characteristic evident in up to 95% of people with ME/CFS. The present study aimed at examining whether two different types of exercise results in changes in health status, circulating elastase activity, interleukin (IL)-1beta and complement C4a levels.

DESIGN: Comparative experimental design.

SETTING: University.

SUBJECTS: Twenty-two women with ME/CFS and 22 healthy sedentary controls.

INTERVENTIONS: participants were subjected to a submaximal exercise (day 8) and a self-paced, physiologically limited exercise (day 16). Each bout of exercise was preceded and followed by blood sampling, actigraphy and assessment of their health status.

RESULTS: Both submaximal exercise and self-paced, physiologically limited exercise resulted in postexertional malaise in people with ME/CFS. However, neither exercise bout altered elastase activity, IL-1beta or complement C4a split product levels in people with ME/CFS or healthy sedentary control subjects (P > 0.05). Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS.

CONCLUSIONS: Submaximal exercise as well as self-paced, physiologically limited exercise triggers postexertional malaise in people with ME/CFS, but neither types of exercise alter acute circulating levels of IL-1beta, complement C4a split product or elastase activity. Further studying of immune alterations in relation to postexertional malaise in people with ME/CFS using multiple measurement points postexercise is required.

 

Source: Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Frémont M, Paul L. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. J Intern Med. 2010 Apr;267(4):418-35. doi: 10.1111/j.1365-2796.2009.02178.x. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2009.02178.x/full (Full article)

 

Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) patients often report symptom flare (SF) for >24 h after moderate exercise (post-ex). We hypothesized that SF is linked to increases in circulating cytokines and CD40 Ligand (CD40L). In 19 CFS patients and 17 controls, mental and physical fatigue and pain symptom ratings were obtained together with serum for 11 cytokines and CD40L before and at 0.5, 8, 24, and 48 h post-ex.

Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL-1beta, IL-12, IL-6, IL-8, IL-10, and IL-13 (p<.05) 8 h post-ex. Low SF patients (n=8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNFalpha (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings.

 

Source: White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010 Jul 1;47(4):615-24. doi: 10.1111/j.1469-8986.2010.00978.x. Epub 2010 Mar 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378647/ (Full article)

 

Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia

Abstract:

The symptoms of chronic fatigue syndrome (CFS) are consistent with cytokine dysregulation. This has led to the hypothesis of immune dysregulation as the cause of this illness. To further test this hypothesis, we did repeated blood sampling for cytokines while patients and matched healthy controls slept in the sleep lab.

Because no one method for assaying cytokines is acknowledged to be better than another, we assayed for protein in serum, message in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs.

We found no evidence of proinflammatory cytokine upregulation. Instead, in line with some of our earlier studies, we did find some evidence to support a role for an increase in interleukin-10, an anti-inflammatory cytokine. Although the changes were small, they may contribute to the common complaint in CFS patients of disrupted sleep.

 

Source: Nakamura T, Schwander SK, Donnelly R, Ortega F, Togo F, Broderick G, Yamamoto Y, Cherniack NS, Rapoport D, Natelson BH. Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia. Clin Vaccine Immunol. 2010 Apr;17(4):582-7. doi: 10.1128/CVI.00379-09. Epub 2010 Feb 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849324/ (Full article)

 

Serum Cytokine Levels in Postinfective Fatigue Syndrome

TO THE EDITOR—Previous studies have sought evidence for a role of abnormal cytokine activity in patients with chronic fatigue syndrome and have had conflicting results [1–3]. These ambiguous results may reflect heterogeneity in groups of patients considered to have chronic fatigue syndrome and variations in assay systems.

We established postinfective fatigue syndrome as the only well-characterized model of the onset and evolution of chronic fatigue syndrome in a prospective cohort of individuals followed up from the onset of acute infection (Dubbo Infection Outcomes Study [DIOS]) [4]. Longitudinally collected clinical data and blood samples from participants in DIOS provide a unique opportunity for nested case-control studies examining the pathophysiology of chronic fatigue syndrome.

We previously reported the lack of association between cytokine production from cultured peripheral blood mononuclear cells and the postinfective fatigue syndrome- related illness in participants in DIOS [5]. We now report a masked analysis of a longitudinal case-control series from DIOS that extended the number of cytokines tested and focused on serum levels.

Twenty patients with acute infection were selected, including 5 patients with serologically confirmed acute Epstein-Barr virus (EBV) infection followed by postinfective fatigue syndrome lasting ⩾6 months, 5 patients with acute infection (not primary EBV but seropositive for EBV) followed by postinfective fatigue syndrome, and 10 matched control subjects with acute EBV infection followed by prompt recovery. Serum samples and clinical data from baseline and from 3–6 months and 9–12 months after onset of infection were analyzed. Serum samples were coded according to case-control status before transfer to the cytokine analysis laboratory.

Thirty-five analytes were measured in serum samples with use of amultiplex immunoassay, including the chemokines leptin, epithelial cell-derived neutrophil-activating peptide 78, eotaxin, growth-regulated oncogene α, interleukin (IL)-8, interferon (IFN)-inducible protein 10, monocyte chemotactic protein 3, monokine induced by gamma IFN, macrophage inflammatory protein 1α, macrophage inflammatory protein 1β, and regulated upon activation normal T cell expressed and secreted; the cytokines IFN-γ, IL-1α, IL-1β, IL-1Ra, IL-4, IL-5, IL-6, IL-7, IL-2, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IL-17F, tumor necrosis factor α, tumor necrosis factor β; and the growth factors nerve growth factor, plate-let-derived growth factor β, transforming growth factor β, vascular endothelial growth factor, fibroblast growth factor β, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor.

All of the study groups were predominantly female and were matched for both sex distribution (by χ2 test, P = .670) and age (by analysis of variance, P = .597). Cytokine data were analyzed by 2-way analysis of variance examining the effects of time and type of case (EBV postinfective fatigue syndrome, non-EBV postinfective fatigue syndrome, or control) and by Spearman’s correlation between symptom scores and cytokine levels. Because of the number of parameters tested, a conservative threshold for statistical significance (P < .005) was used. Results are shown in Table 1

You can read the rest of this article here: http://cid.oxfordjournals.org/content/50/2/278.full

 

Source: Cameron B, Hirschberg DL, Rosenberg-Hassan Y, Ablashi D, Lloyd AR. Serum cytokine levels in postinfective fatigue syndrome. Clin Infect Dis. 2010 Jan 15;50(2):278-9. doi: 10.1086/649546. http://cid.oxfordjournals.org/content/50/2/278.full (Full article)

 

Plasma cytokines in women with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) studies from our laboratory and others have described cytokine abnormalities. Other studies reported no difference between CFS and controls. However, methodologies varied widely and few studies measured more than 4 or 5 cytokines. Multiplex technology permits the determination of cytokines for a large panel of cytokines simultaneously with high sensitivity and with only 30 ul of plasma per sample. No widely accepted laboratory test or marker is available for the diagnosis or prognosis of CFS. This study screened plasma factors to identify circulating biomarkers associated with CFS.

METHODS: Cytokines were measured in plasma from female CFS cases and female healthy controls. Multiplex technology provided profiles of 16 plasma factors including the pro -inflammatory cytokines: tumor necrosis factor alpha (TNFalpha), lymphotoxin alpha (LTalpha), interleukin (IL) – IL-Ialpha, IL-1beta, IL-6; TH1 cytokines: interferon gamma (IFNgamma), IL-12p70, IL-2, IL-15; TH2: IL-4, IL-5; TH17 cytokines, IL-17 and IL-23; anti-inflammatory cytokines IL-10, IL-13; the inflammatory mediator and neutrophil attracting chemokine IL-8 (CXCL8). Analysis by receiver operating characteristic (ROC) curve assessed the biomarker potential of each cytokine.

RESULTS: The following cytokines were elevated in CFS compared to controls: LTalpha, IL-1alpha, IL-1beta, IL-4, IL-5, IL-6 and IL-12. The following cytokines were decreased in CFS: IL-8, IL-13 and IL-15. The following cytokines were not different: TNFalpha, IFNgamma, IL-2, IL-10, IL-23 and IL-17. Applying (ROC) curve analyses, areas under the curves (AUC) for IL-5 (0. 84), LTalpha (0.77), IL-4 (0.77), IL-12 (0.76) indicated good biomarker potential. The AUC of IL-6 (0.73), IL-15 (0.73), IL-8 (0.69), IL-13 (0.68) IL-1alpha (0.62), IL-1beta (0.62) showed fair potential as biomarkers.

CONCLUSION: Cytokine abnormalities are common in CFS. In this study, 10 of 16 cytokines examined showed good to fair promise as biomarkers. However, the cytokine changes observed are likely to more indicative of immune activation and inflammation, rather than specific for CFS. As such, they are targets for herapeutic strategies. Newer techniques allow evaluation of large panels of cytokines in a cost effective fashion.

 

Source: Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009 Nov 12;7:96. doi: 10.1186/1479-5876-7-96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779802/ (Full article)

 

Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses

Abstract:

OBJECTIVES: As heat shock proteins (Hsp) protect the cells against the deleterious effects of oxidative stress, we hypothesized that Hsp expression might be reduced in patients suffering from chronic fatigue syndrome (CFS) who present an accentuated exercise-induced oxidative stress.

DESIGN: This case-control study compared nine CFS patients to a gender-, age- and weight-matched control group of nine healthy sedentary subjects.

INTERVENTIONS: All subjects performed an incremental cycling exercise continued until exhaustion. We measured ventilation and respiratory gas exchange and evoked compound muscle potential (M-wave) recorded from vastus lateralis. Repetitive venous blood sampling allowed measurements of two markers of oxidative stress [thiobarbituric acid reactive substances (TBARS) and reduced ascorbic acid (RAA)], two cytokines (IL-6 and TNF-alpha) and two Hsp (Hsp27 and Hsp70) at rest, during maximal exercise and the 60-min recovery period.

RESULTS: Compared with controls, resting CFS patients had low baseline levels of RAA and Hsp70. Their response to maximal exercise associated (i) M-wave alterations indicating reduced muscle membrane excitability, (ii) early and accentuated TBARS increase accompanying reduced changes in RAA level, (iii) absence of significant increase in IL-6 and TNF-alpha, and (iv) delayed and marked reduction of Hsp27 and Hsp70 variations. The post-exercise increase in TBARS was accentuated in individuals having the lowest variations of Hsp27 and Hsp70.

CONCLUSIONS: The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress, which might result from delayed and insufficient Hsp production.

 

Source: Jammes Y, Steinberg JG, Delliaux S, Brégeon F.Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. J Intern Med. 2009 Aug;266(2):196-206. doi: 10.1111/j.1365-2796.2009.02079.x. Epub 2009 May 19. https://www.ncbi.nlm.nih.gov/pubmed/19457057

 

Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome

Abstract:

The aim of the current study was to investigate the levels of interleukin-6 (IL-6), its soluble receptors (sIL-6R and sgp130) and F(2)-isoprostanes, at rest and during exercise, in patients with chronic fatigue syndrome (CFS).

Six male CFS patients and six healthy controls performed an incremental exercise test to exhaustion and a submaximal exercise bout to exhaustion. Blood samples taken in the submaximal test at rest, immediately post-exercise and 24 h post-exercise were analyzed for IL-6, sIL-6R, sgp130 and F(2)-isoprostanes. A further 33 CFS and 33 healthy control participants gave a resting blood sample for IL-6 and sIL-6R measurement.

During the incremental exercise test only power output at the lactate threshold was lower (P<0.05) in the CFS group. F(2)-isoprostanes were higher (P<0.05) in CFS patients at rest and this difference persisted immediately and 24 h post-exercise. The exercise study found no differences in IL-6, sIL-6R or sgp130 at any time point between groups. In the larger resting group, there were no differences in IL-6 and sIL-6R between CFS and control groups. This investigation has demonstrated that patients with CFS do not have altered plasma levels of IL-6, sIL-6R or sgp130 either at rest or following exercise. F(2)-isoprostanes, however, were consistently higher in CFS patients.

 

Source: Robinson M, Gray SR, Watson MS, Kennedy G, Hill A, Belch JJ, Nimmo MA. Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scand J Med Sci Sports. 2010 Apr;20(2):282-90. doi: 10.1111/j.1600-0838.2009.00895.x. Epub 2009 Apr 13. https://www.ncbi.nlm.nih.gov/pubmed/19422646

 

Astragalus membranaceus flavonoids (AMF) ameliorate chronic fatigue syndrome induced by food intake restriction plus forced swimming

Abstract:

AIM OF THE STUDY: Alteration of immune function may be associated with chronic fatigue syndrome (CFS) and this study reveals the immunoregulatory effect of Astragalus membranaceus flavonoids (AMF).

MATERIALS AND METHODS: CF rats were induced by food intake restriction plus forced swimming for 6 weeks.

RESULTS: An atrophied spleen associated with a significantly decreased spleen/body weight ratio and a reduced spleen cells proliferation was found in CF rats when compared with home cage controls. AMF given orally at 20, 50 and 100 mg/kg body weight once a day consecutively for 6 weeks could recover the reduced cell proliferation. A switch to Th1-dominated immune regulation was observed in CF rats as the cultured splenocytes produced more interleukin-2 (IL-2) but less IL-4 when compared with controls. Supplementation with AMF could significantly counteract the aberrant cytokine production and rats received AMF exhibited higher endurance capacity to swim when compared with those without AMF administration. Checking the spectrum signals confirmed that the three major isoflavones contained in AMF were ononin, formononetin, and demethylhomopterocarpin.

CONCLUSION: Alterations of immune function may be associated with CFS and the tonic effects of AMF against CF may be attributable to balance the abnormal cytokine level by isoflavones.

 

Source: Kuo YH, Tsai WJ, Loke SH, Wu TS, Chiou WF. Astragalus membranaceus flavonoids (AMF) ameliorate chronic fatigue syndrome induced by food intake restriction plus forced swimming. J Ethnopharmacol. 2009 Feb 25;122(1):28-34. doi: 10.1016/j.jep.2008.11.025. Epub 2008 Dec 6. https://www.ncbi.nlm.nih.gov/pubmed/19103273

 

Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients

Abstract:

Chronic fatigue syndrome (CFS) is characterized by immune dysfunctions including chronic immune activation, inflammation, and alteration of cytokine profiles. T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of CFS. IL-17F is one of the pro-inflammatory cytokines secreted by Th17 cells.

We investigated the association between CFS and the frequency of rs763780, a C/T genetic polymorphism leading to His161Arg substitution in the IL-17F protein. The His161Arg variant (C allele) antagonizes the pro-inflammatory effects of the wild-type IL-17F. A significantly lower frequency of the C allele was observed in the CFS population, suggesting that the His161Arg variant may confer protection against the disease. These results suggest a role of Th17 cells in the pathogenesis of CFS.

 

Source: Metzger K, Frémont M, Roelant C, De Meirleir K. Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochem Biophys Res Commun. 2008 Nov 7;376(1):231-3. doi: 10.1016/j.bbrc.2008.08.135. Epub 2008 Sep 5. https://www.ncbi.nlm.nih.gov/pubmed/18774769

 

IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein Barr virus-infection

Abstract:

BACKGROUND: Chronic active Epstein Barr virus (EBV)-infection is characterized by mononucleosis like symptoms including fatigue, lymphadenopathy and/or hepatosplenomegaly and serologic evidence for ongoing EBV replication. Interferon-gamma (IFN-gamma) triggers several antiviral mechanisms in target cells including the induction of indoleamine-2,3-dioxygenase (IDO), which degrades the essential amino acid tryptophan to kynurenine. Because tryptophan is a precursor of the neurotransmitter 5-hydroxytryptamine (serotonin), tryptophan depletion by IDO can cause mood disturbances in patients with chronic immune activation.

METHODS: This study investigated the tryptophan metabolism in 20 patients with chronic active EBV-infection, who were followed up for 4 to 8 months and in 10 healthy age-matched controls. The clinical suspicion of chronic active EBV infection was verified by the presence of circulating antibodies against EBV early antigen (EA) and virus capsid antigen (VCA).

RESULTS: Patients with detectable EBV-DNA had higher serum neopterin (p<0.01) and lower tryptophan concentrations (p=0.01) than EBV-DNA negative patients. Serum concentrations of neopterin, indicating Th-1 mediated immune activation via IFN-gamma, were positively correlated to enhanced tryptophan degradation (rs=0.650, p<0.001) in patients, but not in healthy individuals. Patients suffering from more severe symptoms (as assessed by questionnaires) tended to have aggravated tryptophan degradation.

CONCLUSION: Our data show that EBV viremia is associated with cell-mediated immune activation and increased tryptophan degradation, which may partly account for the symptoms found in this disorder.

 

Source: Bellmann-Weiler R, Schroecksnadel K, Holzer C, Larcher C, Fuchs D, Weiss G. IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein Barr virus-infection. J Affect Disord. 2008 May;108(1-2):171-6. Epub 2007 Oct 22. https://www.ncbi.nlm.nih.gov/pubmed/17945348