Ancient IL-6-STAT5 signaling orchestrates inflammation in jawless vertebrates
Year: 2026
Type: preprint
Abstract: Interleukin-6 (IL-6) is a central regulator of vertebrate immunity, yet its existence in jawless vertebrates has remained obscure because of extreme sequence divergence. The extant jawless vertebrates (lampreys and hagfish), which deploy variable lymphocyte receptors (VLRs) instead of immunoglobulins and T cell receptors, provide a unique window into the earliest interface between cytokines and adaptive immunity. Here, we identify IL-6-like genes in jawless vertebrates by combining computational structural comparisons, phylogenetic reconstruction, and conserved local and long-range synteny analyses. The encoded proteins adopt the canonical four-helix bundle characteristic of immune-related IL-6 family cytokines and align topologically with mammalian IL-6. In sea lamprey, three IL-6 paralogs show distinct leukocyte and tissue expression patterns and are differentially induced by pathogen-associated molecular patterns and skin injury, indicating early functional diversification of IL-6-mediated inflammatory responses. Stimulation of myeloid peritoneal leukocytes with recombinant lamprey IL-6 induces STAT5 phosphorylation and rapid upregulation of SOCS1/3 genes, consistent with an IL-6/STAT5/SOCS regulatory axis. These findings extend the repertoire of immune-related four-helix bundle cytokines to jawless vertebrates and indicate that IL-6-dependent inflammatory programs were already in place before the divergence of VLR-based and Ig/TCR-based adaptive immune systems in vertebrates.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Emory University, Georgia Research Alliance, European Commission, Max-Planck-Gesellschaft, Ministerio de Ciencia e Innovación, Xunta de Galicia, National Institutes of Health, School of Medicine, Emory University, European Regional Development Fund, National Institute of General Medical Sciences
Awards: G265847165, G2973790809, G3133105243, G3207356259, G393177772, G4180247790, G496129201, G5702163051, G5805502524, G589071779, G7317315230, G77244059, Characterization of an Alternative Adaptive Immune System in Hagfish, G9000102939, G9000118633, G9000240667, G9000244213, T Cell Differentiation and Diversification in Jawless Vertebrates
OpenAlex ID: W7150980856