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INVESTIGATIVE REPORT ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica
Involvement of Leukotriene B 4
Released from Keratinocytes in Itchassociated Response to Intradermal Interleukin-31 in Mice
Tsugunobu ANDOH, Ayako HARADA and Yasushi KURAISHI Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
A recent study suggests that interleukin-31( IL-31) exerts its effect via indirect mechanisms rather than through direct stimulation of cutaneous nerves. However, the underlying peripheral mechanisms of IL- 31-induced itch in the skin remain unclear. Therefore, the present study investigated the peripheral mechanisms underlying IL-31-induced itch in mice. IL-31-induced itch-related response was inhibited by anti-allergic drugs( tranilast and azelastine), but not by an H 1 histamine receptor antagonist( terfenadine). Furthermore, a 5-lipoxygenase inhibitor( zileuton), but not a cyclooxygenase inhibitor( indomethacin), and a leuko triene B 4
( LTB 4
) receptor antagonist( CMHVA) attenuated the action of IL-31. IL-31 receptor-immunoreactivity was observed in the epidermis and primary sensory neurones. IL-31 receptor mRNA was expressed in mouse keratinocytes and dorsal root ganglia neurones. IL-31 increased the production of LTB 4 in mouse keratinocytes. These results suggest that IL-31 elicits itch not only through direct action on primary sensory neurones, but also by inducing LTB 4 production in keratinocytes. Key words: itch; leukotriene B 4
; interleukin-31; keratinocytes; scratching; dorsal root ganglia. Accepted May 16, 2017; Epub ahead of print May 17, 2017 Acta Derm Venereol 2017; 97: 922 – 927.
Corr: Tsugunobu Andoh, Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-1094, Japan. E-mail: andoht @ pha. u-toyama. ac. jp
Itch( or pruritus), an unpleasant skin sensation that evokes the desire to scratch, is the most common symptom of dermatitis( e. g. atopic dermatitis) and certain systemic disorders( e. g. cholestasis). Histamine from the mast cells has been thought to play an essential role in itch.
H 1 histamine receptor antagonists are the drugs of first choice for the treatment of itch. However, many severe pruritic diseases, except acute urticaria, respond poorly to H 1 histamine receptor antagonists( 1 – 3). Therefore, the underlying mechanisms and mediators of itch in most pruritic diseases are unclear.
Interleukin-31( IL-31), a cytokine released from T cells( especially, CD4 +-Th2 cells), signals through a receptor complex comprising IL-31RA and oncostatin M receptor β( OSMRβ)( 4, 5). IL-31 plays a major role in the induction of chronic inflammation in diseases such as dermatitis, allergic rhinitis and asthma( 6). In particular, the expression of IL-31 mRNA is elevated in the skin of patients with atopic dermatitis( 7, 8) as well as in animal models of atopic dermatitis( 9) and contact dermatitis( 10). IL-31 induces skin inflammation( 5) and scratching, an itch-associated response( 11). However, in animal models of atopic dermatitis, the administration of anti-IL-31 antibody inhibited spontaneous scratching, but not dermatitis( 12). These findings suggest that IL-31 is a mediator of itch.
The peripheral mechanisms of IL-31-induced pruritus are not completely clear. A recent study showed that IL- 31 increases the intracellular Ca 2 + ion concentration in the primary cultures of mouse dorsal root ganglia( DRG) neurones, suggesting that IL-31 directly activates primary afferents and induces itch sensation( 13). However, IL-31 receptor complex is expressed not only in DRG neurones, but also in several immune cells( e. g. activated monocytes, macrophages, eosinophils, and basophils) and keratinocytes( 4). A recent study showed that IL-31 exerts its pruritic effect indirectly via keratinocytes and secondary mediators rather than through the stimulation of its receptors on cutaneous nerves( 14). In addition, our previous studies on the peripheral mechanisms of itch have shown the important role of keratinocytes and their itch mediators, including leukotriene B 4
( LTB 4
)( 15 – 18). Therefore, this study investigated the involvement of
LTB 4 in peripheral mechanism of IL-31-induced itch.
MATERIALS AND METHODS Animals
Male ICR mice aged 4 – 11 weeks were used in this study. The mice were purchased from Japan SLC( Shizuoka, Japan). For one part of the experiment, neonatal mice were used for the isolation of cutaneous keratinocytes. Neonatal mice were obtained from late pregnant mice purchased from Japan SLC( Shizuoka). They were housed in a room with controlled temperature( 21 – 23 ° C), humidity( 45 – 65 %), and light( on from 07.00h to 19.00h). Food and water were freely available. All experimental procedures involving animals were approved by the Committee for Animal Experiments at the University of Toyama and conducted in accordance with the guidelines of the Japanese Pharmacological Society.
Drugs
Recombinant mouse IL-31 was prepared in Chugai Pharmaceutical Co., Ltd( Shizuoka, Japan). Briefly, IL-31 was purified from the supernatant of mouse IL-31-transformed Chinese hamster ovary cells using hydroxyapatite column( Bio-Rad Laboratories, Inc., Hercules, CA, USA), anion-exchange column( GE healthcare, Chicago, IL, USA), and gel filtration column( GE healthcare). IL-31 was dis- doi: 10.2340 / 00015555-2697 Acta Derm Venereol 2017; 97: 922 – 927
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2017 Acta Dermato-Venereologica.