IL-6

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Ligands
IL-6 (Human)

GtoPdb Ligand ID: 4998

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 [14]. 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.

Species: Human

View interactive charts of activity data across species

Immunopharmacology Comments
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 [6]. 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 [15] (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 [3]. 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 [16]. 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 [19].

Immunopharmacology Comments

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 [6]. 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 [15] (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 [3]. 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 [16].

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 [19].

Immunopharmacology Disease
Disease	X-Refs	Comment	References
Rheumatoid arthritis	Disease Ontology: DOID:7148 OMIM: 180300	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.
Asthma	Disease Ontology: DOID:2841 OMIM: 600807	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).	4,11,18,20