Tracing the origins of IL-6 cytokines: evidence from the sea lamprey 9398

Abstract Description The adaptive immune system of jawless vertebrates, such as the sea lamprey (Petromyzon marinus), differs from that of jawed vertebrates by using variable lymphocyte receptors (VLRs) instead of immunoglobulins, yet these are expressed in B-like and T-like cell populations. Despite this, conserved elements such as cytokines and their receptors orchestrate immune responses across vertebrates. Interleukin-6 (IL-6), a key inflammatory mediator in jawed vertebrates, has remained elusive in jawless vertebrates, likely due to poor sequence conservation. We identified three IL-6-like candidate genes in the sea lamprey that exhibit hallmark IL-6 features. These genes encode short (∼200 amino acid) proteins with predicted four-helical cytokine structures and signal peptides. Expression profiling indicates predominant transcription in immune tissues. Single-cell RNA-seq of unstimulated white blood cells reveals that only one IL-6-like gene is expressed, mainly in granulocytes. Functional assays show a strong upregulation of these genes in the ammocoete typhlosole/gut after intraperitoneal flagellin injection. We are generating recombinant proteins for further functional assays, including ligand–receptor interaction and cell stimulation. These findings suggest IL-6-like cytokines in jawless vertebrates may be pivotal to their unique immune system, bridging innate immune signaling and VLR-mediated adaptive responses, providing insights into the evolutionary origins of vertebrate immunity. Funding Sources This study was supported by National Institutes of Health Grants R01AI072435 and R35GM122591. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)