Unusual levels of Interleukin-10 in Chronic Fatigue Syndrome


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I found this article interesting:
Deficiency of IL-10 in Chronic Fatigue Syndrome?

A new 2015 study, published in the Mediators of Inflammation journal suggests a deficiency of interleukin (IL)-10 in chronic fatigue syndrome (CFS).

Chronic fatigue syndrome/myalgic encephalomyelitis, an illness characterized by unexplained fatigue lasting 6 months or more, is often linked to dysfunctional neuroendocrine and immune responses, including abnormal production of several cytokines (NG Klimas & A O’Brien Koneru, 2007). The term CFS was introduced in 1988 but an umbrella term – neuroendocrine-immune dysfunction syndrome (CNDS) is also often used (LA Jason et al., 2003).

The ‘immune hormone’ IL-10 is a major anti-inflammatory cytokine in periphery and the central nervous system (CNS). IL-10 downregulates the pro-inflammatory immune responses related to the T helper (Th1) cell axis, and, in general, the production of most of the pro-inflammatory cytokines. This includes a suppression of cytokine production and the expression of cytokine receptors in brain’s microglia cells (M Sawada et al., 1999).

In the Mediators of Inflammation study, D. Peterson and colleagues from the Simmaron Research, NV, USA and the Griffith University, Parklands, Australia collected cerebrospinal fluid (CSF) samples from CFS patients at the time of diagnosis, and cytokines were analyzed via the Bio-Plex Pro Human Cytokine 27-plex Assay (Bio-Rad).

The authors report that of the 27 cytokines examined; only IL-10 was significantly decreased in the CFS group, as compared to healthy control individuals. Further studies may be required to identify and/or confirm whether the putative IL-10 deficiency may contribute to increased pro-inflammatory activities in CFS.

This next article also mentions varying IL-10 levels in ME/CFS patients:

"Runaway immune system may play role in chronic fatigue syndrome"

MONDAY, Dec. 17, 2018 -- Researchers say they've pinpointed a possible culprit in chronic fatigue syndrome (CFS), reporting that an overactive immune system might send the entire body into an overwhelming state of exhaustion.

"For the first time, we have shown that people who are prone to develop a CFS-like illness have an overactive immune system, both before and during a challenge to the immune system," said lead researcher Alice Russell, from King's College London.

"Our findings suggest that people who have an exaggerated immune response to a trigger may be more at risk of developing CFS," Russell added.

People with chronic fatigue syndrome -- also called myalgic encephalomyelitis -- experience extreme tiredness. The causes of the condition remain unclear, but many patients say their condition began after their immune system fought off an infection.

One problem in trying to determine the causes of chronic fatigue syndrome is that it's impossible to assess patients before the illness develops. In this study, researchers used a model for chronic fatigue syndrome based on the hepatitis C treatment interferon-alpha.

Interferon-alpha triggers immune system activity in much the same way as a major infection does, the study authors explained in a college news release. Many patients who receive interferon-alpha develop acute fatigue during treatment and some have fatigue that lasts for more than six months after treatment ends.

In the new study, the researchers assessed fatigue and immune system activity in 55 patients before, during and after treatment with interferon-alpha. The investigators discovered differences between the immune systems of 18 patients who developed long-term fatigue and those who had a normal recovery.

Those 18 patients had a much stronger immune response during treatment with interferon-alpha, with a doubling in the levels of immune system messenger molecules called interleukin-10 and interleukin-6, according to the report.

Even before treatment started, levels of interleukin-10 were higher among the 18 patients who later developed long-term fatigue, suggesting the immune system may have been primed to overreact, the study authors explained.

Yet, there was no difference before treatments between the groups in their levels of fatigue or in psychiatric symptoms, like depression or recent stressful events, the scientists noted. The study findings were published Dec. 17 in the journal Psychoneuroendocrinology.

According to senior researcher Carmine Pariante, "A better understanding of the biology underlying the development of CFS is needed to help patients suffering with this debilitating condition. Although screening tests are a long way off, our results are the first step in identifying those at risk and catching the illness in its crucial early stages."

Further research is needed to confirm that the findings from patients treated with interferon-alpha would also apply to people with chronic fatigue syndrome, and to better understand the factors that may be driving an exaggerated immune response, the study authors said.
This is the second article I've seen about interleukin-10 and CFS, however, another study found a deficiency of IL-10 in some CFS patients.

Here's information on interleukin-10:
Interleukin 10

From Wikipedia, the free encyclopedia

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene.[5] IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins.[6] Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.[6]

Gene and protein structure
The IL-10 protein is a homodimer; each of its subunits is 178-amino-acid long.[7]

IL-10 is classified as a class-2 cytokine, a set of cytokines including IL-19, IL-20, IL-22, IL-24 (Mda-7), IL-26 and interferons type-I (IFN-alpha, -beta, -epsilon, -kappa, -omega), type-II (IFN-gamma) and type-III (IFN-lambda,[8] also known as IL-28A, IL-28B, and IL-29).[9]

Expression and synthesis
In humans, IL-10 is encoded by the IL10 gene, which is located on chromosome 1 and comprises 5 exons,[5] and is primarily produced by monocytes and, to a lesser extent, lymphocytes, namely type 2 T helper cells (TH2), mast cells, CD4+CD25+Foxp3+ regulatory T cells, and in a certain subset of activated T cells and B cells. IL-10 can be produced by monocytes upon PD-1 triggering in these cells.[10] IL-10 upregulation is also mediated by GPCRs, such as beta-2 adrenergic[11] and type 2 cannabinoid[12] receptors. The expression of IL-10 is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora.[13] IL-10 expression is tightly regulated at the transcriptional and post-transcriptional level. Extensive IL-10 locus remodeling is observed in monocytes upon stimulation of TLR or Fc receptor pathways.[14] IL-10 induction involves ERK1/2, p38 and NF-κB signalling and transcriptional activation via promoter binding of the transcription factors NF-κB and AP-1.[14] IL-10 may autoregulate its expression via a negative feed-back loop involving autocrine stimulation of the IL-10 receptor and inhibition of the p38 signaling pathway.[15] Additionally, IL-10 expression is extensively regulated at the post-transcriptional level, which may involve control of mRNA stability via AU-rich elements[16] and by microRNAs such as let-7[17] or miR-106.[18]

IL-10 is a cytokine with multiple, pleiotropic, effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. IL-10 can block NF-κB activity, and is involved in the regulation of the JAK-STAT signaling pathway.

Discovered in 1991[19] IL-10 was initially reported to suppress cytokine secretion, antigen presentation and CD4+ T cell activation.[20][21][22][23] Further investigation has shown that IL-10 predominantly inhibits lipopolysaccharide (LPS) and bacterial product mediated induction of the pro-inflammatory cytokines TNFα,[24] IL-1β,[24] IL-12,[25] and IFNγ[26] secretion from Toll-Like Receptor (TLR) triggered myeloid lineage cells.

Effect on tumors
Over time a more nuanced picture of IL-10's function has emerged as treatment of tumor bearing mice has been shown to inhibit tumor metastasis.[27] Additional investigation by multiple laboratories has generated data that further supports IL-10's immunostimulatory capacity in an immunoncology context. Expression of IL-10 from transfected tumor cell lines[28][29] in IL-10 transgenic mice[30] or dosing with IL-10 leads to control of primary tumor growth and decreased metastatic burden.[31][32] More recently, PEGylated recombinant murine IL-10 (PEG-rMuIL-10) has been shown to induce IFNγ and CD8+ T cell dependent anti-tumor immunity.[33][34] More specifically, PEGylated recombinant human IL-10 (PEG-rHuIL-10) has been shown to enhance CD8+ T cell secretion of the cytotoxic molecules Granzyme B and Perforin and potentiate T cell receptor dependent IFNγ secretion.[35]

Role in disease
A study in mice has shown that IL-10 is also produced by mast cells, counteracting the inflammatory effect that these cells have at the site of an allergic reaction.[36]

IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such as IFN-γ, IL-2, IL-3, TNFα and GM-CSF made by cells such as macrophages and Th1 T cells. It also displays a potent ability to suppress the antigen-presentation capacity of antigen presenting cells; however, it is also stimulatory towards certain T cells (Th2) and mast cells and stimulates B cell maturation and antibody production.

IL-10 checks the inducible form of Cyclo-oxygenase, Cyclo-oxygenase-2 (COX-2). Lack of IL-10 has been shown to cause COX activation and resultant Thromboxane receptor activation to cause vascular endothelial and cardiac dysfunctions in mice. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age.[37]

IL-10 is linked to the myokines, as exercise provokes an increase in circulating levels of IL-1ra, IL-10, and sTNF-R, suggesting that physical exercise fosters an environment of anti-inflammatory cytokines.[38][39]

Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals.[40] Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme.[41] As a result, TNFα levels rise and result in inflammation.[42] TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.[42]

In melanoma cell lines, IL-10 modulates the surface expression of NKG2D ligands.[43]

I also recommend reading the following, since it explains the basics about cytokines and inflammatory responses:

Th1 and Th2 responses: what are they?
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