Targeting classical IL-6 signalling or IL-6 trans-signalling in depression?
Michael Maes1, George Anderson, Marta Kubera
1Deakin University, Department of Psychiatry , Geelong , Australia dr.michaelmaes@hotmail.com.
Expert Opinion on Therapeutic Targets
|February 20, 2014
Summary
Interleukin-6 (IL-6) trans-signalling contributes to depression. Targeting this pathway with soluble glycoprotein 130 (sgp130) inhibitors, rather than broad IL-6 blockers, may offer a more effective treatment strategy for depression.
Area of Science:
- Neuroimmunology
- Psychiatry
- Pharmacology
Background:
- Elevated levels of Interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) have been observed in patients with depression for over two decades.
- IL-6 exerts pro-inflammatory effects primarily through IL-6 trans-signalling via sIL-6R, contrasting with the anti-inflammatory role of membrane-bound IL-6 receptor (IL-6R) signalling.
Purpose of the Study:
- To review the role of IL-6 and sIL-6R in inflammation and depression.
- To explore the biological mechanisms linking IL-6 trans-signalling to depression.
- To evaluate potential therapeutic strategies targeting IL-6 signalling in depression.
Main Methods:
- Review of existing data on IL-6 and sIL-6R in inflammation and depression.
- Analysis of animal models of depression.
- Examination of the effects of various antidepressant classes on IL-6 signalling.
Main Results:
- IL-6 trans-signalling is implicated in depression pathogenesis through pathways including the acute phase response, zinc and erythron disorders, HPA axis activation, and oxidative stress.
- Psychosocial stressors and inflammatory conditions are associated with depression onset, highlighting a multifactorial aetiology.
Conclusions:
- Broad IL-6 inhibition (e.g., tocilizumab) may not be optimal for depression due to IL-6's homeostatic functions.
- Inhibiting IL-6 trans-signalling by increasing soluble glycoprotein 130 (sgp130) activity, while preserving membrane IL-6R signalling, presents a promising therapeutic avenue.
- Further research is needed on sgp130Fc combined with antidepressants in animal models of chronic depression.
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