In a comprehensive review published in Nature Reviews Immunology, one of the most respected scientific journals, our team synthesised emerging insights into how cytokines are regulated through their structural assembly.
Cytokines are small signalling proteins released by immune cells that act as messengers, allowing cells to communicate. They coordinate immune responses, tissue repair and many other biological processes. Because cytokines can act on many different cell types and trigger diverse responses, their activity must be tightly controlled.
Such regulation occurs at multiple levels, including the quantities of cytokines that are produced, how they are modified post-synthesis and how they engage receptors on their target cells. Breakdown of this regulation can lead to disease.
Excessive cytokine activity can drive chronic inflammation and autoimmune disorders, while insufficient signalling can weaken the body's ability to fight infections or cancer.
Notably, cytokines are already important therapeutic targets in diseases such as rheumatoid arthritis, inflammatory bowel disease and cancer. However, current approaches often lack precision and can cause unwanted side effects.
More precise cytokine regulation
In this work, Dr Ina Rudloff and a team from Hudson Institute of Medical Research examined an increasingly recognised mechanism of cytokine regulation known as multimerisation, i.e. the ability of cytokines to assemble into pairs or larger molecular complexes. These include homodimers (two identical molecules), heterodimers (two different molecules) and higher-order multimers.
"By synthesising findings from across multiple cytokine families, we show that these structural arrangements fundamentally influence cytokine bioactivities," Dr Rudloff said.
"For example, some cytokines such as interleukin-10 and interferon-g must form homodimers for full bioactivity. In contrast, interleukin-6, which is usually active as a discrete monomer, can form dimers that alter how it signals and reduce its ability to activate receptors."
"Our own work demonstrated that homodimer formation of the anti-inflammatory cytokine interleukin‑37 limits its activity, i.e. acts as a natural 'brake'. Preventing this dimerisation enhances IL-37's anti-inflammatory functions, highlighting how structural assembly can directly control biological outcomes," she said.
Biological outcomes depend on cytokine structure
This review was jointly supervised by senior authors Professors Marcel and Claudia Nold from Hudson Institute and Monash University, and Associate Professor Andrew Ellisdon from Monash Biomedicine Discovery Institute.
They said these examples illustrate that the same cytokine can exert different effects depending on its structural state, adding an additional layer of regulation to signalling pathways that can affect almost any biochemical process in the body.
"By bringing together structural, biological and translational insights, our review highlights how understanding cytokine multimerisation opens up new opportunities to improve cytokine-based therapies," they said.
"Designing cytokines in specific structural forms, for example stabilising active configurations or preventing inhibitory ones, may allow fine-tuning of pathway regulation with greater precision."
This emerging approach, often referred to as cytokine engineering, has the potential to enable safer and more effective treatments across a wide range of immune-mediated diseases.
