Interleukin-6 (IL6), a 26-kD secreted protein, is a key member of the pro-inflammatory cytokine family. It stimulates B cells to produce antibodies and has pleiotropic functions including roles in the regulation of the immune and nervous systems, liver regeneration, and metabolic control [1,2,4]. IL6 signaling occurs through three modes: classic signaling via membrane-bound IL-6 receptor (mIL-6R), trans-signaling via soluble IL-6 receptor (sIL-6R), and trans-presentation. These pathways, mediated by the formation of complexes with mIL-6R or sIL-6R and the signal-transducing subunit molecule gp130, lead to its diverse functions [2,4]. Genetic models, such as KO/CKO mouse models, are valuable for studying IL6's functions.

In a murine multiple trauma model, modulation of IL6 signaling (both classic and trans-signaling) was attempted. IL6 and sIL6-R levels rapidly peaked after fracture and more markedly after polytrauma. Blocking IL6 signaling via IL6-R antibody application significantly reduced these parameters, neutrophil infiltration in shock organs, and end-organ damage. This shows the regulatory role of IL6 signaling pathways in polytrauma, with hemorrhagic shock being a major trigger of the inflammatory response [3]. In colon carcinoma, although tumor cells, T cells, and myeloid cells all express IL6, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are the primary IL6-expressing cell type. Knocking out IL6 in colon tumor cells did not significantly alter tumor growth in wild-type (WT) mice, while overexpression of IL6 in colon tumor cells increased tumor growth in vivo. This indicates that a high local IL6 threshold in the tumor is essential for IL6-mediated tumor promotion [5].

In conclusion, IL6 is a multifunctional cytokine involved in immune regulation, inflammation, and various physiological processes. Mouse models, like those in trauma and cancer studies, have revealed its role in inflammatory responses and tumor growth. Understanding IL6's functions through these models can potentially lead to better treatment strategies for diseases related to abnormal IL6 signaling, such as inflammatory and autoimmune disorders, and cancer [2,3,5].

References:

1. Kang, Sujin, Narazaki, Masashi, Metwally, Hozaifa, Kishimoto, Tadamitsu. . Historical overview of the interleukin-6 family cytokine. In The Journal of experimental medicine, 217, . doi:10.1084/jem.20190347. https://pubmed.ncbi.nlm.nih.gov/32267936/

2. Uciechowski, Peter, Dempke, Wolfram C M. 2020. Interleukin-6: A Masterplayer in the Cytokine Network. In Oncology, 98, 131-137. doi:10.1159/000505099. https://pubmed.ncbi.nlm.nih.gov/31958792/

3. Malysch, Tom, Reinhold, Jens Michael, Becker, Christopher A, Schmidt-Bleek, Katharina, Kleber, Christian. 2022. In vivo immunomodulation of IL6 signaling in a murine multiple trauma model. In Immunologic research, 71, 164-172. doi:10.1007/s12026-022-09319-3. https://pubmed.ncbi.nlm.nih.gov/36151360/

4. Rose-John, Stefan. 2012. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. In International journal of biological sciences, 8, 1237-47. doi:10.7150/ijbs.4989. https://pubmed.ncbi.nlm.nih.gov/23136552/

5. Ibrahim, Mohammed L, Lu, Chunwan, Klement, John D, Smith, Alyssa D, Liu, Kebin. 2020. Expression profiles and function of IL6 in polymorphonuclear myeloid-derived suppressor cells. In Cancer immunology, immunotherapy : CII, 69, 2233-2245. doi:10.1007/s00262-020-02620-w. https://pubmed.ncbi.nlm.nih.gov/32488308/