Interleukin-6 in SARS-CoV-2 induced disease: Interactions and therapeutic applications

Abstract

Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease.

Keywords: C-reactive protein (CRP); Cancer; Cytokine storm; Hypoxia; Inflammation; Interleukin-6 (IL-6); Pneumonia; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Tocilizumab.

Fig. 1

Interleukin (IL)−6 receptor/ligand interactions. IL-6 interacts with two types of IL receptors (IL-6Rs): (a) Interaction with membranous form directs classic cis-signaling pathway, whereas interaction with the soluble form (i.e. sIL-6R) promotes trans-signaling pathway (b). The trans-membrane protein gp-130 acts as a subunit for IL-6R, transducing signals toward cytosol. IL-6/IL-6R/gp-130 interactions transduce signals via janus kinas (JAK) and signal transducer and activator of transcription 3 (STAT3). STAT3 is further transferred toward the nucleus in order to promote activation of target gens, such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)−1α. Inhibition of membrane-bound and soluble IL-6Rs by agents like acetolizumab is of therapeutic importance in cancer patients and cases with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced disease. (c) Interleukin (IL)−6 amplifier in patients with SARS-CoV-2 induced disease. The activity of NF-κβ is induced by IL-6/STAT-3. NF-κβ, in turn, promotes IL-6 transcription and its release toward the extracellular milieu. This mechanism of implication will intensify the severity of condition in patients with high activity of IL-6, such what seen in SARS-CoV-2 induced disease. (d) IL-6 inducible effect on SARS-CoV-2 cellular entry. SARS-CoV-2 interacts with angiotensin-converting enzyme 2 (ACE2) receptor in order to enter the cellular cytosol. Recognition of the ACE2 by the virus and its membrane infusion is mediated by cathepsin L. IL-6 induces the activity of ACE2 and cathepsin L, thus facilitating cellular entry of the virus.

Fig. 2

Cytokine storm in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients experience a hyperinflammatory state called cytokine storm. SARS-CoV-2 stimulates the activity of CD4⁺ T cells and their conversion into T helper (Th)−1 cells. The pathogenic Th1 cells release a number of factors including granulocyte-macrophage colony-stimulating factor (GM-CSF) that act for stimulation of inflammatory monocytes and macrophages. The inflammatory monocytes and macrophages intrude lung environment through leaky vessels mediated by vascular endothelial growth factor (VEGF) released from endothelial cells (ECs) of blood vessels. Among a number of factors released from monocytes, over-release of interleukin (IL)−6 takes important roles in the excessive cytokine release. High presence of IL-6 in the area will turn the tissue nearby into developing hypoxia and further damages to lung alveoli and capillary bed, manifested by EC disruption. This will hamper efficient delivery of oxygen, thereby causing shortness of breath, chest thickness and respiratory failure. Fibrotic lungs seen in imaging systems is a result of tissue damage in lung parenchyma. The hypoxic environment also facilitates promotion of coagulopathy-related events.

Fig. 3

Serge of interleukin (IL)−6, cytokine storm and multi-organ injury.

Fig. 4

Interleukin (IL)−6 mediated immunosuppressive tumor microenvironment (TME). IL-6 is released from a number of pro-tumor cells in TME including cancer-associated fibroblasts (CAFs), cancer cells, macrophage type 2 (M2) cells and endothelial cells (ECs). High release of this cytokine into the TME mediates conversion of cancer cells into cancer stem cells (CSCs), promotes natural killer (NK) cell dysfunction, M2 polarity and suppresses dendritic cell (DC) differentiation. The outcomes of such modality in the TME are tumor aggression and therapy resistance.

Fig. 5

Interleukin (IL)−6 in cancer patients who also have SARS-CoV-2 induced disease. The activity of anti-tumor T helper 1 (Th1) cells is reduced in tumors. By contrast, pro-tumor Th2 cells are active and promote anti-inflammatory and immunosuppressive signals. The resultant immunosuppression is indicative of lower extent of cytokine storm, and presumably lower extent of SARS-CoV-2 related damages in cancer patients. Th1 cells represent a hyperactive state in response to the factors like IL-6 released as a response to the severe SARS-CoV-2 induced disease, rendering systemic antiviral responses. However, a hyperactive cell type generally shows an exhausted state, which means the final decapitation for T cell-based immunity. Signals from T cells seen in patients with SARS-CoV-2 induced disease may be an explanation for further immunosuppression. Taken together, it seems that cancer patients are at the higher risk of experiencing damages due to SARS-CoV-2 compared with non-tumor patients who have active SARS-CoV-2 induced disease. Another interpretation is that SARS-CoV-2 may change tumor ecosystem into a more aggressive phenotype. Star indicates a hyperactive state, and the question mark represents uncertainty of the SARS-CoV-2 action on Th2 cell activity.