Distinct and context-dependent immunobiology of interleukin (IL)-36, IL-37, and IL-38: A comparative review

Interleukin (IL)-36, IL-37, and IL-38 belong to the newer members of the IL-1 cytokine family that exert diverse and context-dependent immune functions. IL-36α/β/γ are predominantly pro-inflammatory cytokines, whereas IL-37 and IL-38 function mainly as anti-inflammatory mediators with distinct regulatory properties. Despite growing interest, key aspects of their biology remain unresolved, including differences between intracellular and extracellular activity, tissue-specific effects, and receptor engagement, particularly for IL-38. Here, we provide a comparative review of IL-36, IL-37, and IL-38, summarizing their cell-type-specific expression, receptor interactions, intracellular versus extracellular function, post-translational maturation and relevance in autoimmune, inflammatory, infectious and metabolic diseases. By highlighting shared and divergent features of these cytokines we identified gaps requiring further clarification to fully understand how IL-36, IL-37, and IL-38 shape either immune homeostasis or drive pathology.