Tag: interleukins

Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS.

Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups.

Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

Source: Kegan J. Moneghetti, Mehdi Skhiri, Kévin Contrepois, Yukari Kobayashi, Holden Maecker, Mark Davis, Michael Snyder, Francois Haddad & Jose G. Montoya. Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Scientific Reports volume 8, Article number: 2779 (2018). doi:10.1038/s41598-018-20941-w. Received:02 November 2017. Accepted:26 January 2018. Published online:09 February 2018. https://www.nature.com/articles/s41598-018-20941-w (Full article)

Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment

Abstract:

BACKGROUND: Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades.

METHODS: Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a ‘proximity extension assay’ (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA.

RESULTS: In CFS/ME patients, the ‘normalized protein expression’ value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls.

CONCLUSIONS: In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra.

TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014.

Source: Roerink ME, Knoop H, Bronkhorst EM, Mouthaan HA, Hawinkels LJAC, Joosten LAB, van der Meer JWM. Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment. J Transl Med. 2017 Dec 29;15(1):267. doi: 10.1186/s12967-017-1371-9. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1371-9 (Full article)

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways

Abstract:

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels.

This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity.

Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS.

Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms.

HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.

 

Source: Morris G, Anderson G, Maes M. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol. 2016 Oct 20. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27766535

 

Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome

Abstract:

BACKGROUND: The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1β and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue.

METHODS: We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated.

RESULTS: Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1β and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1β production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1β levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1β levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered.

CONCLUSIONS: These findings suggest that LPS-induced fatigue is an IL-1β-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.

 

Source: Zhang ZT, Du XM, Ma XJ, Zong Y, Chen JK, Yu CL, Liu YG, Chen YC, Zhao LJ, Lu GC. Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome. J Neuroinflammation. 2016 Apr 5;13(1):71. doi: 10.1186/s12974-016-0539-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822300/ (Full article)

 

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay.

Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1β, suggesting a disturbance in interleukin 1 signaling.

Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

 

Source: Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31. https://www.ncbi.nlm.nih.gov/pubmed/25824300

 

Sleep, neuroimmune and neuroendocrine functions in fibromyalgia and chronic fatigue syndrome

Abstract:

The justification for disordered chronobiology for fibromyalgia and chronic fatigue syndrome (CFS) is based on the following evidence: The studies on disordered sleep physiology and the symptoms of fibromyalgia and CFS; the experimental studies that draw a link between interleukin-1 (IL-1), immune-neuroendocrine-thermal systems and the sleep-wake cycle; studies and preliminary data of the inter-relationships of sleep-wakefulness, IL-1, and aspects of peripheral immune and neuroendocrine functions in healthy men and in women during differing phases of the menstrual cycle; and the observations of alterations in the immune-neuroendocrine functions of patients with fibromyalgia and CFS (Moldofsky, 1993b, d). Time series analyses of measures of the circadian pattern of the sleep-wake behavioural system, immune, neuroendocrine and temperature functions in patients with fibromyalgia and CFS should determine whether alterations of aspects of the neuro-immune-endocrine systems that accompany disordered sleep physiology result in nonrestorative sleep, pain, fatigue, cognitive and mood symptoms in patients with fibromyalgia and CFS.

 

Source: Moldofsky H. Sleep, neuroimmune and neuroendocrine functions in fibromyalgia and chronic fatigue syndrome. Adv Neuroimmunol. 1995;5(1):39-56. http://www.ncbi.nlm.nih.gov/pubmed/7795892

 

Fibromyalgia, sleep disorder and chronic fatigue syndrome

Abstract:

Various research studies show that the amalgam of disordered sleep physiology, chronic fatigue, diffuse myalgia, and cognitive and behavioural symptoms constitutes a non-restorative sleep syndrome that may follow a febrile illness, as in the chronic fatigue syndrome. Where rheumatic complaints are prominent such a constellation of disturbed sleep physiology and symptoms also characterizes the fibromyalgia disorder.

In contrast to the chronic fatigue syndrome, fibromyalgia is associated with a variety of initiating or perpetuating factors such as psychologically distressing events, primary sleep disorders (e.g. sleep apnoea, periodic limb movement disorder) and inflammatory rheumatic disease, as well as an acute febrile illness.

The chronic fatigue syndrome and fibromyalgia have similar disordered sleep physiology, namely an alpha rhythm disturbance (7.5-11 Hz) in the electroencephalogram (EEG) within non-rapid eye movement (NREM) sleep that accompanies increased nocturnal vigilance and light, unrefreshing sleep. Aspects of cytokine and cellular immune functions are shown to be related to the sleep-wake system.

The evidence suggests a reciprocal relationship of the immune and sleep-wake systems. Interference either with the immune system (e.g. by a viral agent or by cytokines such as alpha-interferon or interleukin 2) or with the sleeping-waking brain system (e.g. by sleep deprivation) has effects on the other system and will be accompanied by the symptoms of the chronic fatigue syndrome.

 

Source: Moldofsky H. Fibromyalgia, sleep disorder and chronic fatigue syndrome. Ciba Found Symp. 1993;173:262-71; discussion 272-9. http://www.ncbi.nlm.nih.gov/pubmed/8491102