Increased IL-6 and soluble IL-6 receptor (sIL-6R) levels in depressed patients was first shown over 20 years ago. The pro-inflammatory effects of IL-6 are predominantly mediated by IL-6 trans-signalling via the sIL-6R, whereas IL-6R membrane signalling has anti-inflammatory effects.We review data on IL-6 and sIL-6R in inflammation, depression, animal models of depression and the effects of different classes of antidepressants. The biological context for IL-6 trans-signalling as a pathogenic factor in depression involves its role in the acute phase response, disorders in zinc and the erythron, hypothalamic-pituitary-adrenal axis activation, induction of the tryptophan catabolite pathway, oxidative stress, bacterial translocation, transition towards sensitisation, autoimmune processes and neuroprogression and the multicausal aetiology of depression, considering that psychosocial stressors and comorbid immune-inflammatory diseases are associated with the onset of depression.The homeostatic functions of IL-6 imply that ubiquitous IL-6 inhibitors, for example, tocilizumab, may not be the optimal treatment target in depression. A more promising target may be to increase soluble glycoprotein 130 (sgp130) inhibition of IL-6 trans-signalling, while allowing the maintenance of IL-6R membrane signalling. Future research should delineate the effects of treatments with sgp130Fc in combination with antidepressants in various animal models of chronic depression.
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