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

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.

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.

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.

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.