Cytokine Signaling Mechanisms in Inflammation and Disease

Cytokines are small secreted proteins that orchestrate immune and inflammatory responses by binding to specific receptors on target cells. Signalling through membrane-bound receptors typically activates intracellular cascades such as the Janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor-κB and mitogen-activated protein kinase pathways. An additional layer of complexity arises when cytokines bind soluble forms of their receptors, a process known as trans-signalling, which extends responsiveness to cells lacking the membrane receptor. This duality underpins both protective host-defence functions—against pathogens and in tissue repair—and pathological processes in chronic inflammation, autoimmunity, fibrosis and cancer. Key cellular players include macrophages, neutrophils and specialised T cell subsets such as TH17 cells, which produce interleukin-17 and other effectors. Recent advances in single-cell and spatial transcriptomics have revealed dynamic cytokine-mediated cross-talk between immune and stromal cells within diseased tissues. Translational efforts now focus on selectively inhibiting pro-inflammatory trans-signalling or modulating receptor isoform expression to achieve therapeutic benefit without compromising essential homeostatic functions.

Research from Nature Portfolio

Single-cell RNA sequencing, T cell receptor profiling and spatial transcriptomics have identified a circulating population of TH17 intermediates that express high levels of interleukin-26. Upon infiltration into psoriatic skin, these IL-26+ cells induce transforming growth factor-β1 expression in basal keratinocytes, thereby driving their own maturation into IL-17A-producing TH17 effectors. This paracrine feedback loop provides a detailed mechanistic framework for how early TH17 subsets establish and amplify local inflammation via epithelial crosstalk, offering new targets for intervention in chronic skin disease.

Cytokine Signaling Mechanisms in Inflammation and Disease publication trend

The graph below shows the total number of articles in cytokine signaling mechanisms in inflammation and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine: small protein secreted by immune cells that modulates intercellular communication and immune responses.

JAK/STAT pathway: intracellular signalling cascade in which Janus kinases phosphorylate STAT transcription factors to regulate gene expression.

Classic signalling: activation of a cell via binding of a cytokine to its membrane-bound receptor.

Trans-signalling: activation of cells lacking the membrane receptor by a cytokine–soluble receptor complex associating with a signal-transducing subunit.

TH17 cells: subset of CD4+ T helper lymphocytes characterised by production of interleukin-17 and involvement in barrier immunity and autoimmunity.

Paracrine signalling: communication between neighbouring cells through the local release of soluble mediators.

References

1. The IL-17 family in diseases: from bench to bedside. Signal Transduction and Targeted Therapy (2023).
2. Differentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis. Nature Communications (2023).
3. Interleukin 11 therapy causes acute left ventricular dysfunction. Cardiovascular Research (2024).
4. Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling. Cell Communication and Signaling (2019).