IL-6 is a pleiotropic cytokine with important role in immune regulation, hematopoiesis, inflammation and oncogenesis (1,2). IL-6-type cytokines exert their action via the signal transducer gp130 that associates with IL6R in a cooperative manner to form a hexameric signal transducing complex, capable of activating the down stream mediators of this signalling pathway (3,4,5,6,7). This mechanism of signal transduction is shared by other members of the IL-6 type cytokines like IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1 that use gp130 as a common subunit of the signal transducing complex (7).

IL-6 stimulation leads to the activation of JAK/STAT pathway (8,9). Both STAT1 and STAT3 are phosphorylated and are able to form homo- and heterodimers after activation leading to their nuclear localization and subsequent regulation of transcription of respective target genes (8,9,10). SHP-2 is one of the ubiquitous tyrosine phosphatases and IL-6 stimulation leads to the SHP2-dependent activation of MAPKs, it also links the Grb2–SOS complex and Gab1 to gp130 (11,12,13). Phosphorylated Gab1 acts as an adapter and is involved in the indirect association of SHP-2 and PI-3 kinase (13). Downstream activation of Vav1, Rac-1 and MAP2K4 is necessary for the IL-6-mediated STAT3 phosphorylation and transactivation to accomplish its effects. (12). STAT3 is also phosphorylated by PKCD and it causes inhibition of STAT3 DNA binding and transcriptional activity (14). PTPN11 and SOCS3 exert inhibitory function and thus lead to down regulation of the signalling cascade.(15,16,17)

References:

1. Kishimoto, T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res. Ther. 2006. 8. S2.

2. Kishimoto T et al. IL-6: from its discovery to clinical applications. Int Immunol. 2010. 5, 347-52. Epub 2010 Apr 21. Review

3. Taga, T., Hibi, M., Hirata, Y. et al. Interleukin-6 triggers the
association of its receptor with a possible signal transducer,
gp130. Cell. 1989. 58, 573.

4. Murakami, M., Hibi, M., Nakagawa, N. et al. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 1993. 260, 1808.

5. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex.; Boulanger MJ; Chow DC; Brevnova EE; Garcia KC; Science; 2003;

6. Taga T et al. Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 1997. 15, 797–819.

7. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G. and Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003. 374, 1-20.

8. Shizuo Akira. IL-6-regulated Transcription Factors . Int. J. Biochm. Cell Bid. 1997. 29(12). 1401-1418.

9. Heinrich, P. C., Behrmann, I., M¨uller-Newen, G., Schaper, F. and Graeve, L. IL-6-type cytokine signalling through the gp130/JAK/STAT pathway. Biochem. J. 1998. 334,
297–314.

10. Zhong, Z., Wen, Z. and Darnell, J. E. Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994. 264:95.

11.Holgado-Madruga, M., Emlet, D. R., Moscatello, D. K., Godwin, A. K. and Wong, A. J. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature. 1996. 379, 560–564.

12. Schuringa, J. J., Dekker, L. V., Vellenga, E. and Kruijer, W. Sequential activation of Rac-1, SEK-1/MKK-4, and protein kinase Cδ is required for interleukin-6-induced STAT3 Ser-727 phosphorylation and transactivation. J. Biol. Chem. 2001. 276, 27709–27715.

13. Takahashi-Tezuka M, Yoshida Y, Fukada T, Ohtani T, Yamanaka Y, Nishida K, Nakajima K, Hibi M, Hirano T. Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase. Mol Cell Biol. 1998. 7, 4109-17.

14. Jain, N., Zhang, T., Kee, W. H., Li, W. and Cao, X. Protein kinase Cδ associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J. Biol. Chem. 1999. 274, 24392–24400

15. Naka, T., Narazaki, M., Hirata, M. et al. Structure and
function of a new STAT-induced STAT inhibitor. Nature. 1997. 387:924.

16. Endo, T. A., Masuhara, M., Yokouchi, M. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 1997. 387:921.

17. Schmitz J; Weissenbach M; Haan S; Heinrich PC and Schaper F. SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130. J Biol Chem; 2000.