Cytokines are chemical messengers that help the body get rid of invading bacteria and viruses, and control inflammation. The body carefully balances cytokines because they are instrumental in keeping the immune system healthy. However, this balance can be upset if the immune system overreacts.

For example, a serious infection or a severe burn can unleash a cytokine storm —also called cytokine release syndrome (CRS)— in which the body produces too many cytokines. In turn, the elevated levels of a mixture of common cytokines * result in acute systemic, life-threatening, hyper-inflammation which is characterized by high fever and severe organ dysfunction.

Double-edge sword
Cytokine release syndrome (CRS) is, in fact, a double-edged sword. While CRS may be helpful in controlling tumors, viruses, and infections, the hyper-inflammation is harmful to the host-patient.

Interleukin-6 (IL-6)
Interleukin-6 (IL-6) helps drive inflammation that damages the body, making it a key cytokine in CRS. This cytokine also delivers its message by fastening to IL-6 receptors within cells, instructing cells to spread inflammation. Because IL-6 is important in CRS, treatments that block the IL-6 signal can relieve inflammation. However, this blocking tends to be long-lasting and leads to adverse effects.

Researchers from Osaka University have discovered a way to block IL-6 signals while minimizing treatment side effects.  The outcomes of the study were published in the Proceedings of the National Academy of Sciences (PNAS).

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In their study, the researchers interrupted the inflammatory signal using an antibody that briefly blocks the IL-6 receptor. The brief interruption was long enough to protect the tissues against injury caused by sepsis or severe burns.

Figure 1.0: Giving medication a short half-life anti-IL-6 to patients of Sepsis, ARD, Burns, etc. is expected to suppress vascular damage or secondary infection. Photo courtesy: Osaka University.

“Our results suggest that CRS can be treated with an IL-6 receptor antibody that has a short half-life,” explained the study’s lead author Sujin Kang, Ph.

“This can prevent vascular damage and at the same time reduce the side effects associated with blocking IL-6,” Kang added,

Vascular damage
Vascular damage happens when an infection causes the cells that line the inner surface of blood vessels to become leaky. The leaking fluid triggers a cytokine storm and can cause a secondary infection. The group also reported a potential mechanism for this damage to cells. When IL-6 binds to its receptor it activates a protein called hypoxia-inducible factor-1α (HIF1α), which amplifies inflammation.

“We found that blocking the IL-6R–HIF1α signal strengthened vascular endothelial cells and improved vessel integrity. This helped to prevent leakage from the vessels and relieved the inflammation caused by CRS,” explains senior author Tadamitsu Kishimoto, MD,

“We hope this will help patients suffering from CRS and other inflammatory diseases in the future,” Kishimoto added

Other diseases that can cause CRS include sepsis and acute respiratory distress syndrome, COVID-19 infection, and ischemia. People with traumatic injuries and those taking some cancer immunotherapies can also experience CRC.

The findings of this study can hopefully provide an alternative therapeutic approach to patients with these conditions.

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Note * Cytokines include can be generally divided into three groups: antitumor effectors (granzyme B (GZMB), interferon gamma (IFN-γ), macrophage inflammatory protein (MIP)-1α, and tumor necrosis factor (TNF)-α), stimulatory and regulatory cytokines (GM-CSF, interleukin (IL)-2, MCP-1, NO, and IL-15), and inflammatory cytokines (IL-1, IL-6, and IL-17A).

Reference
[1] Kang S, Onishi S, Ling Z, Inoue H, Zhang Y, Chang H, Zhao H, Wang T, Okuzaki D, Matsuura H, Takamatsu H, Oda J, Kishimoto T. Gp130-HIF1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling. Proc Natl Acad Sci U S A. 2024 Jan 9;121(2):e2315898120. doi: 10.1073/pnas.2315898120. Epub 2024 Jan 2. PMID: 38165930; PMCID: PMC10786312.

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