The Evolution of IL6-IL6R-JAK-STAT Signaling Pathway in Metazoan

Background: The Interleukin-6 (IL6)–Interleukin-6 receptor (IL6R)–Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway plays a crucial role in innate immunity by inducing the production of various immune effectors. However, its stepwise evolutionary assembly across metazoans remains incompletely characterized. Methods: This study systematically screened 18 metazoan phyla or subphyla for the presence of IL6 family cytokines, their receptors, JAKs, and STATs. Phylogenetic relationships were constructed using Neighbor-Joining methods, and domain architectures were predicted via SMART. Results: IL6 was found only in vertebrates, whereas IL6R could be traced to Mollusca. JAK and STAT appeared early in Porifera. IL6R, JAK1/2, STAT1 and STAT5A/B first co-existed in Mollusca. The IL-6 co-receptor gp130 was detected in fish, but was not reliably detected in available reptiles’ and birds’ genomes. Conclusions: The IL6-IL6R-JAK-STAT pathway was assembled incrementally: JAK and STAT were first detected in Porifera, IL6R was added in Mollusca to form the IL6R-JAK-STAT module, and finally, most IL6 family cytokines were present in vertebrates (fish). These findings might provide a pre-existing molecular framework that facilitated the subsequent evolution of the complete pathway in vertebrates. Collectively, this study provides a comprehensive evolutionary framework for the stepwise assembly of the IL6-IL6R-JAK-STAT signaling pathway across metazoans.