IL-6 signal transduction and its physiological roles: the signal orchestration model

Rev Physiol Biochem Pharmacol. 2003;149:1-38. doi: 10.1007/s10254-003-0012-2. Epub 2003 Apr 5.


Interleukin (IL)-6 is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs. In a target cell, IL-6 can simultaneously generate functionally distinct or sometimes contradictory signals through its receptor complex, IL-6Ralpha and gp130. One good illustration is derived from the in vitro observations that IL-6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated STAT3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects. The final physiological output can be thought of as a consequence of the orchestration of the diverse signaling pathways generated by a given ligand. This concept, the signal orchestration model, may explain how IL-6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances. Elucidation of the molecular mechanisms underlying this issue is a challenging subject for future research. Intriguingly, recent in vivo studies indicated that the SHP-2-binding site- and YXXQ-mediated pathways through gp130 are not mutually exclusive but affect each other: a mutation at the SHP-2-binding site prolongs STAT3 activation, and a loss of STAT activation by gp130 truncation leads to sustained SHP-2/ERK MAPK phosphorylation. Although IL-6/gp130 signaling is a promising target for drug discovery for many human diseases, the interdependence of each signaling pathway may be an obstacle to the development of a nonpeptide orally active small molecule to inhibit one of these IL-6 signaling cascades, because it would disturb the signal orchestration. In mice, a consequence of the imbalanced signals causes unexpected results such as gastrointestinal disorders, autoimmune diseases, and/or chronic inflammatory proliferative diseases. However, lessons learned from IL-6 KO mice indicate that IL-6 is not essential for vital biological processes, but a significant impact on disease progression in many experimental models for human disorders. Thus, IL-6/gp130 signaling will become a more attractive therapeutic target for human inflammatory diseases when a better understanding of IL-6 signaling, including the identification of the conductor for gp130 signal transduction, is achieved.

Publication types

  • Review

MeSH terms

  • Acute-Phase Reaction / immunology
  • Amino Acid Sequence
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / physiology
  • Autoimmune Diseases / immunology
  • Bone and Bones / immunology
  • Bone and Bones / metabolism
  • Cytokine Receptor gp130
  • Hematopoiesis / immunology
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology*
  • MAP Kinase Signaling System / immunology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology
  • Models, Immunological*
  • Molecular Sequence Data
  • Mutation
  • Neoplasms / immunology
  • Neurosecretory Systems / immunology
  • Phenotype
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / physiology
  • Signal Transduction / immunology*


  • Antigens, CD
  • IL6ST protein, human
  • Interleukin-6
  • Membrane Glycoproteins
  • Receptors, Interleukin-6
  • Cytokine Receptor gp130