Cytokine storm – insights into new treatments


A key player in the cytokine storm is Interleukin-6 (IL-6), which contributes to inflammation and tissue damage. IL-6 exerts its effects by binding to IL-6 receptors on cells, instructing them to promote inflammation. Blocking the IL-6 signal can alleviate inflammation in cytokine release syndrome (CRS); however, this approach often comes with long-lasting side effects.

Cytokines play a crucial role in the body’s defence against bacteria and viruses, as well as in regulating inflammation. Maintaining a balanced cytokine level is essential for a healthy immune system. However, this balance can be disrupted if the immune system reacts excessively, leading to a cytokine storm, which involves an overproduction of cytokines and results in severe, life-threatening inflammation.

In a recent study, researchers identified a method to block IL-6 signals with minimized side effects (Figure 1). They utilized an antibody that temporarily blocked the IL-6 receptor, providing a short-term interruption to the inflammatory signal. This brief intervention proved sufficient to protect tissues from damage caused by cytokine storms triggered by conditions such as sepsis or severe burns.

Figure 1: Endothelial gp130–HIF1α signaling mediates proinflammatory responses and PAI-1 production. (A) Gene expression of HUVECs induced by LPS+sIL-6R stimulation assessed by RNA-seq. Upstream regulator analysis of genes upregulated in HUVECs under LPS+sIL-6R stimulation. All datasets were examined by Ingenuity Pathway Analysis (Qiagen Bioinformatics). (B) Flow cytometry analysis of gp130 expression after siRNA transfection. (C) Cells were treated with si-IL6ST for 48 h following combined stimulation, and the indicated gene expressions were analyzed by quantitative real-time PCR (qRT-PCR). (D and E) Cells were pretreated with PX-478 (80 μM) for 4 h followed by LPS+sIL-6R stimulation for 24 h, and IL-6, IL-8, and PAI-1 expression levels were analyzed by qRT-PCR (D) and ELISA (E). *P < 0.05, **P < 0.01, ***P < 0.005. P-values were determined using unpaired, two-tailed Student’s t tests. Data are representative of three (B, D, and E) independent experimental replicates and are presented as means ± SD.

The findings suggest that an IL-6 receptor antibody with a short half-life could be an effective treatment for CRS, preventing vascular damage and simultaneously reducing side effects associated with prolonged IL-6 blockade. The researchers observed that blocking the IL-6R–HIF1α signal enhanced the strength of vascular endothelial cells, improving vessel integrity and preventing inflammation caused by CRS.

Journal article: Kang, S., et al., 2023. Gp130–HIF1α axis–induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling. Proceedings of the National Academy of Sciences.

Summary by Stefan Botha

International Union of Immunological SocietiesUniversity of South AfricaInstitute of Infectious Disease and Molecular MedicineElizabeth Glazer Pediatric Aids Foundation