Interleukin-1

From: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/">Interleukin-1 as a mediator of fatigue in disease: a narrative review</a>

In this review, we first described the mechanism by which IL-1 is able the influence certain brain regions, thereby leading to the development of fatigue. Next, we reviewed the literature describing studies where (i) fatigue was correlated to IL-α, IL-1β, or IL-1Ra activity or (ii) the effect of lowering IL-1 concentrations on fatigue severity was measured. In addition to inflammatory diseases such as CAPS, we also focused on non-inflammatory diseases characterized by profound fatigue, such as several malignancies and CFS. There might be a distinctive underlying mechanism causing fatigue in inflammatory disorders, compared to the other groups of fatigue causing illnesses. In inflammatory diseases, fatigue often has an acute pattern; however, in subgroups of patients, fatigue persists even when the inflammation phase has subsided.

It can be concluded that there is no solid evidence that increased concentrations of circulating IL-α and IL-1β are associated with fatigue in any of the diseases described. This is not surprising, given the fact that circulating concentrations of these cytokines usually are very low, as discussed previously [<a id="tag_583982135" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR12">12</a>]. However, IL-1Ra seems to be correlated with fatigue in some diseases, for example in cancer. However, in each of the studies described in this review, but especially in CFS, studies are rather contradicting. For a large part, this can be caused by the fact that there is a large heterogeneity between studies. Selection of controls and sample handling, which is known to be very important when measuring cytokines, differed significantly between studies or was not described [<a id="__tag_583982102" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR143">143</a>]. Furthermore, studies differed with respect to questionnaires used to measure fatigue, the presence of comorbid diseases, the use of medication in the patients studied, sample size, time since onset of the disease, duration of the fatigue (acute versus chronic), and the presence or absence of inflammatory processes.

For blocking IL-1 activity, most of the currently available inhibitors do not reach effective concentrations in the brain when the blood brain barrier is intact. This particularly is the case for the large molecular inhibitors (like canakinumab and rilonacept). For anakinra, which has a smaller molecular weight of 17 kDa, the available pharmacological data show that the drug is able to reach the CNS after peripheral administration, although it is not clear if the local concentration in the CNS is high enough to have a substantial influence on neural processes [<a id="tag_583982107" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR144">144</a>, <a id="__tag_583982056" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR145">145</a>].

In diseases such as rheumatoid arthritis [<a id="tag_583982131" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR2">2</a>] and Sjögren’s syndrome [<a id="tag_583982083" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR3">3</a>], blocking IL-1 using anakinra reveals promising effects on fatigue. In addition, specific inhibition of either IL-1α [<a class=" bibr popnode" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR109">109</a>] or IL-1β [<a id="tag_583982169" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR4">4</a>] also has a positive influence on fatigue severity. Unfortunately, the majority of the studies were not randomized controlled trials [<a id="tag_583982087" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR2">2</a>, <a id="tag_583982177" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR4">4</a>] or were most likely underpowered to detect significant effects [<a id="__tag_583982093" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR3">3</a>]. If IL-1 blockade effectively diminishes fatigue, the question of course remains whether this is a direct effect on central fatigue, whether the effect on fatigue is due to inhibition of inflammation, or whether IL-1 blockade directly affects central neurotransmitter systems. Also, it is important to determine if the positive effects of IL-1 blockade are limited to acute fatigue or are also present in patients who report persistent fatigue without evidence of being ill. Especially in this last group, persistent fatigue may involve maintenance of alterations in central brain systems, potentially triggered by acute inflammation.

With regard to future studies, it is our hope that these will be performed in more controlled settings, which will make it easier to draw conclusions and to establish whether fatigue should or should not be added to the growing list of diseases in which blocking IL-1 is effective [<a id="tag_583982112" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/#CR146">146</a>].