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Synonyms: B-cell stimulatory factor 2 | CTL differentiation factor | hybridoma growth factor | interferon β2 | interleukin-6
Compound class: Endogenous peptide in human, mouse or rat
Comment: IL-6 is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. It is the originating member of a family of related cytokines that include IL-11, oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine factor 1/B-cell stimulating factor 3 (NNT-1), neuropoietin (NPN), IL-27, and IL-31 . IL-6 is produced by T and B cells, macrophages, dendritic cells, and non-immune cells such as fibroblasts, endothelial cells, glial cells, keratinocytes, and placental syncytio- and extravillous trophoblasts.
The receptors for these cytokines (except IL-31) share a common signal transducing subunit gp130 (IL6ST).
IL-6 is a critical regulator of the immune system and has been widely implicated in autoimmune disease, infection responses and in the regulation of metabolic, regenerative, and neural processes.
Ligand Activity Visualisation Charts
These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.✖
|IL-6 signalling in monocytes and macrophages is pro-inflammatory. It is produced by these cell types in response to infection and traumatic tissue injury. In contrast, the IL-6 produced by exercising muscle produces an anti-inflammatory effect. Antibodies and other agents that inhibit the IL-6 signalling pathway are in development as immunomodulators for the treatment of rheumatoid arthritis (RA), and other inflammatory and autoimmune diseases . The mAb siltuximab is already approved. Investigational agents include sirukumab, clazakizumab, olamkicept, gerilimzumab (an anti-IL-6 mAb with a high potency and long half-life, which has the potential to support low and infrequent dosing- beginning Phase 2 trial NCT02795299 for methotrexate or TNF-α antagonist resistant RA), and olokizumab  (CDP6038) a RA Phase 2 clinical candidate [8,17].
There is evidence to suggest that IL-6 in the cerebrospinal fluid may be linked to the emergence of depressive symptoms that are often associated with systemic inflammation . Additional evidence showing that treatment with anti-IL-6 antibodies (sirukumab or siltuximab) reduces despressive symptoms in patients being given these agents as therapy for inflammatory diseases, supports this proposed mechanism in depression .
SARS-CoV-2 and COVID-19: Elevated IL-6 has been considered to be an important mediator of the dysfunctional immune response and cytokine storm that is proposed to contribute to the development of severe COVID-19 [1,10]. Based on this evidence existing drugs that target the IL-6/IL-6R pathway are being investigated for efficacy in hospitalised COVID-19 patients. The RECOVERY and REMAP-CAP trials found evidence that the IL-6R monoclonals tocilizumab and sarilumab were effective in severe COVID-19, and in July 2021 the WHO recommended their use in patients with severe or critical COVID-19 .
|IL-6 is known to drive arthritic inflammation and bone destruction in RA. mAbs against both the IL-6 ligand and its receptor (IL-6R) are now approved for use in the clinic, and accumulating evidence suggests that targeting of IL-6 can be the best treatment option for RA. In light of this, development of new monoclonal antibodies targeting the IL-6/IL-6R pathway is continuing.
|IL-6 is an important regulator of immune responses and has been implicated in the pathogenesis of asthma. Genome-wide association studies have revealed that genes specific to IL-6 signalling are associated with an increased asthma risk (Ferreira et al., 2011). Increased levels of IL-6 have been reported in the serum of patients with asthma (Yokoyama et al., 1995). Sputum concentrations of IL-6 show an inverse relationship with lung function in asthmatics (Morjaria et al., 2011). Elevated lung epithelial IL-6 levels have been detected in asthmatic patients with increasing disease severity and are probably a characteristic of the pathobiological processes in mucosal airway inflammation in severe asthma (Uddin et al., 2013).
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