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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 .