Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide b-endorphin, via STAT3 ⁄calcium axis in atopic dermatitis

Atopic dermatitis (AD), a common chronic inflammatory skin disease prevalent in 6–9% of the general population, is increasing globally.¹ It is characterized by severe itch and is usually associated with a personal or family history of atopic diseases. The itch affects physical growth, mental development, emotional equanimity and performance at school and work.² The predominance of itch in patients with AD makes it ideal for studying the pathophysiology of pruritus‐like itches. Antihistamines have little effect on alleviating AD itch, suggesting histamine is not a major mediator of AD itch.³, ⁴ Neuropeptides, proteinases, arachidonic derivatives and cytokines may contribute to AD pruritus.³, ⁵ Opioids such as morphine may induce severe itching.⁶ An incidence of pruritus of 10–50% has been reported in people administered opioids intravenously,⁷, ⁸ and an incidence of 20–100% with neuraxial administration. Interestingly, naloxone, an antidote for morphine, suppresses itch in patients with chronic renal failure and AD.⁹

Blood levels of β‐endorphin, which binds to opioid receptors, have been associated with intensity of subjective itch in patients with AD.²β‐Endorphin and its receptors are both present in keratinocytes and free nerve endings.¹⁰ Increases in endorphin are also inhibited in patients with AD treated with psoralen plus ultraviolet (UV) A.¹⁰ Furthermore, the cytokine interleukin (IL)‐1 and UV radiation, both known to accentuate itch in AD, enhance the release of β‐endorphin from keratinocytes.¹¹, ¹² Although the peripheral role of endorphins on induction of itch through the peripheral μ‐opioid receptor has not been verified in the literature, indirect evidence suggests that β‐endorphin might be closely associated with itch in AD.

Cytokines are considered an important mediator in AD, but little is known about how cytokines in AD contribute to the production of peripheral β‐endorphin in AD skin. The transgenic overexpression of the cytokine IL‐31 in lymphocytes in mice induces severe pruritus and dermatitis.¹³ It is expressed preferentially by T helper (Th) 2 cells, and it activates a heterodimeric receptor composed of IL‐31 receptor A (IL‐31RA) and oncostatin M receptor (OSMR), both found on epithelial cells and keratinocytes.¹³, ¹⁴ The epidermis of patients with AD has an increased expression of IL‐31RA and IL‐31.¹⁵, ¹⁶ IL‐31 can induce the production of several proinflammatory mediators, including epidermal growth factor, vascular endothelial growth factor and monocyte chemotactic protein‐1, in bronchial alveolar cells.¹⁷ Blood IL‐31 level has been correlated to disease severity in patients with AD.¹⁸ Although both IL‐31 and opioid pathways are enhanced in AD skin, no study has investigated their relationship in AD. To do this, we performed an in vitro study in which we added various doses of IL‐31 into primary keratinocytes of normal foreskins and measured the release of endorphins using enzyme‐linked immunosorbent assay (ELISA) and the expression of STAT (signal transducer and activator of transcription) 3, ERK (extracellular signal‐regulated kinase) and JNK (c‐Jun N‐terminal kinase) by Western blotting. We also performed two in vivo studies, one to measure blood levels of IL‐31 and β‐endorphin in patients with AD recruited from a dermatological clinic in a tertiary centre and normal controls, and the other to measure the colocalization of IL‐31RA and β‐endorphin in skin samples from the study group and normal controls. In addition, we measured the colocalization of IL‐31RA and β‐endorphin in the skin of TPA (12‐O‐tetradecanoylphorbol 13‐acetate)‐painted mice, a model for irritant contact dermatitis. The results of this study might further advance our understanding of the regulatory mechanisms underlying peripheral itch in AD.