Journal Club 2014.12.29

TRPA1 channels mediate acute neurogenic
inflammation and pain produced by bacterial
endotoxins
Victor Meseguer1
, Yeranddy A. Alpizar2, Enoch Luis1
, Sendoa Tajada3, Bristol Denlinger1
, Otto Fajardo1
,Jan-Albert Manenschijn1
, Carlos Ferna´ndez-Pen˜a1
, Arturo Talavera2,4, Tatiana Kichko5, Bele´n Navia6,
Alicia Sa´nchez2, Rosa Sen˜arı´s6, Peter Reeh5, Marı´a Teresa Pe´rez-Garcı´a3, Jose´ Ramo´n Lo´pez-Lo´pez3,
Thomas Voets2, Carlos Belmonte1
, Karel Talavera1,2,* & Fe´lix Viana1,*

Gram-negative bacterial infections are accompanied by inflammation and somatic or
visceral pain. These symptoms are generally attributed to sensitization of nociceptors
by inflammatory mediators released by immune cells. Nociceptor sensitization during
inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway
by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS
exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential
cation channel that is critical for transducing environmental irritant stimuli into nociceptor
activity. Moreover, we find that pain and acute vascular reactions, including neurogenic
inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel
activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The
identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers
new insights into the pathogenesis of pain and neurovascular responses during bacterial
infections and opens novel avenues for their treatment.

journal club – 2014.12.15.

A natural dye, Niram improves atopic dermatitis through down-regulation of TSLP

Na-Ra Hana, Jin-Young Parkb, Jae-Bum Jangb, Hyun-Ja Jeongc,∗, Hyung-Min Kima,∗∗

a Department of Pharmacology, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea
b Regional Innovation Center and Inflammatory Disease Research Center, Hoseo University, 165, Sechul-ri, Baebang-myun, Asan, Chungnam 336-795, Republic of Korea

c Department of Food Technology, Biochip Research Center, and Inflammatory Disease Research Center, Hoseo University, 165, Sechul-ri, Baebang-myun, Asan, Chungnam 336-795,Republic of Korea

Naju Jjok (Polygonum tinctorium Lour.) has been known to treat skin diseases in traditional Korean medicine. A natural textile dye, Niram made from Naju Jjok has traditionally been used to dye clothes. Thymic stromal lymphopoietin (TSLP) plays an important role in the development of atopic dermatitis (AD). Thus, we investigated that Niram might amelio- rate AD through regulation of TSLP. Niram significantly inhibited the levels of TSLP through blockade of caspase-1/receptor-interacting protein 2 pathway in stimulated mast cells. Fur- ther, Niram ameliorated clinical symptoms in AD mouse. Niram significantly inhibited the infiltration of inflammatory cells in lesional skin. The levels of TSLP, caspase-1, IL-4, and IL-6 were inhibited in lesional skin applied topically with Niram. Niram significantly inhibited the serum levels of IgE and histamine in AD mouse. Finally, Niram significantly inhibited the levels of TSLP in polyriboinosinic polyribocytidylic acid-stimulated human keratinocyte HaCaT cells. These results establish Niram as a functional dye embracing the aspects of not only a traditional use but also a pharmacological effect.

© 2014 Elsevier B.V. All rights reserved.

Keywords : Niram, TSLP, Caspase-1, Mast cell, Atopic dermatitis, NC/Nga mice

journal club 2014.12.01

Antipruritic mechanisms of topical E6005, a phosphodiesterase 4 inhibitor: Inhibition of responses to proteinase-activated receptor 2 stimulation mediated by increase in intracellular cyclic AMP

Abstract

Background

Phosphodiesterase 4 (PDE4), which catalyses the conversion of cyclic adenosine 3′,5′-monophosphate (cAMP) to 5′-AMP, plays a critical role in the pathogenesis of inflammatory disorders. Pruritus is the main symptom of dermatitides, such as atopic dermatitis, and is very difficult to control. Recent studies have shown that the activation of proteinase-activated receptor 2 (PAR2) is involved in pruritus in dermatoses in humans and rodents.

Objective

To investigate the inhibitory effect of E6005, a topically effective PDE4 inhibitor, on PAR2-associated itching in mice.

Methods

Mice were given an intradermal injection of SLIGRL-NH2 (100 nmol/site), a PAR2 agonist peptide, into the rostral part of the back. E6005 and 8-bromo-cAMP were applied topically and injected intradermally, respectively, to the same site. Scratching bouts were observed as an itch-related behavior, and firing activity of the cutaneous nerve was electrophysiologically recorded. Keratinocytes were isolated from the skin of neonatal mice and cultured for in vitro experiments. The concentrations of cAMP and leukotriene B4 (LTB4) were measured by enzyme immunoassay. The distribution of PDE4 subtypes in the skin was investigated by immunostaining.

Results

Topical E6005 and intradermal 8-bromo-cAMP significantly inhibited SLIGRL-NH2-induced scratching and cutaneous nerve firing. Topical E6005 increased cutaneous cAMP content. Topical E6005 and intradermal 8-bromo-cAMP inhibited cutaneous LTB4 production induced by SLIGRL-NH2, which has been shown to elicit LTB4-mediated scratching. E6005 and 8-bromo-cAMP inhibited SLIGRL-NH2-induced LTB4 production in the cultured murine keratinocytes also. PDE4 subtypes were mainly expressed in keratinocytes and mast cells in the skin.

Conclusions

The results suggest that topical E6005 treatment inhibits PAR2-associated itching. Inhibition of LTB4 production mediated by an increase in cAMP may be partly involved in the antipruritic action of E6005.

Abbreviations

  • cAMP, cyclic adenosine 3′,5′-monophosphate;
  • EIA, enzyme immunoassay;
  • IgG, immunoglobulin G;
  • LTB4, leukotriene B4;
  • PDE, phosphodiesterase;
  • PAR2, proteinase-activated receptor 2;
  • PBS, phosphate-buffered saline

dec presentation

Scroll to Top