Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis

Abstract

RA is a chronic, systemic, autoimmune disease characterized by inflammation and degradation of the joints, causing significant negative impact on quality of life. In addition to joint disease, symptoms and co-morbidities associated with RA-namely pain, fatigue and mood disorders-are often as debilitating as the disease itself. The pro-inflammatory cytokine IL-6 plays a critical role in RA-associated pathology. However, a greater understanding of the translational effects of IL-6 outside of the immune system is needed. This review discusses our current understanding of emerging aspects of IL-6 in RA-associated pain, fatigue and mood disorders such as depression and anxiety. This review also describes the clinical effects of IL-6 inhibition on these symptoms and co-morbidities in patients with RA.

Fig. 1

Signalling of IL-6 via the classical and trans-signalling pathways In classical signalling, IL-6 binds membrane-bound receptors on a few peripheral cells, including hepatocytes and leucocytes. The IL-6/IL-6R complex does not result in signalling, as association with the ubiquitously expressed transducing protein gp130 is required to initiate signalling. In trans-signalling, membrane-bound IL-6R is made soluble by cleavage with metalloproteases. Soluble IL-6R binds IL-6 to form the IL-6/IL-6R complex, which then binds membrane-bound gp130. This form of trans-signalling does not require membrane-bound IL-6R and can therefore occur in any cell type that expresses membrane-bound gp130, including cells of the CNS, neurons, astrocytes and microglia. gp130: glycoprotein 130; JAK: Janus kinase; STAT: signal transducer and activator of transcription; mIL-6Rα: membrane-bound IL-6 receptor alpha; sIL-6Rα: soluble IL-6 receptor alpha.

Fig. 2

The HPA axis in RA Pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β stimulate cortisol and CRH release by acting at all three levels of the HPA axis (solid green lines). As a result, glucocorticoids regulate their own production through negative feedback on the upper levels of the HPA axis, including CRH in the PVN of the hypothalamus and ACTH in the anterior pituitary (dashed red lines). ACTH: adrenocorticotropic hormone; CRH: corticotropin-releasing hormone; PVN: paraventricular nucleus.

Fig. 3

Conceptual model of interactions between fatigue, pain and mood in RA RA disease activity is associated with widespread inflammation, largely mediated by the pro-inflammatory cytokine IL-6. Pain, fatigue and inflammation act as stressors that may influence both mental health and hyperalgesia/central sensitization. In some patients these manifestations can have major implications for mood, thereby negatively impacting quality of life.