Croton Oil-induced Irritant Contact Dermatitis Research Articles

Oleic acid exhibits an expressive anti-inflammatory effect in croton oil-induced irritant contact dermatitis without the occurrence of toxicological effects in mice

Ethnopharmacological relevanceCutaneous inflammatory diseases, such as irritant contact dermatitis, are usually treated with topical corticosteroids, which cause systemic and local adverse effects limiting their use. Thus, the discovery of new therapeutic alternatives able to effectively treat skin inflammatory disorders, without causing adverse effects, is urgently needed.Aim of the study: To investigate the topical anti-inflammatory effect of oleic acid (OA), a monounsaturated fatty acid, into Pemulen® TR2-based semisolid dosage forms, employing a croton oil-induced irritant contact dermatitis model in mice. Materials and methodsMale Swiss mice were submitted to skin inflammation protocols by acute and repeated applications of croton oil. The anti-inflammatory activity of Pemulen® TR2 hydrogels containing OA was evaluated by assessing oedema, inflammatory cell infiltration, and pro-inflammatory cytokine IL-1β levels. The mechanisms of action of OA were evaluated using cytokine IL-1β application or pretreatment with the glucocorticoid antagonist mifepristone. Possible toxic effects of OA were also assessed. ResultsPemulen® TR2 3% OA inhibited the acute ear oedema [maximal inhibition (Imax) = 76.41 ± 5.69%], similarly to dexamethasone (Imax = 84.94 ± 2.16%), and also inhibited ear oedema after repeated croton oil application with Imax = 85.75 ± 3.08%, similar to dexamethasone (Imax = 81.03 ± 4.66%) on the day 7 of the experiment. Croton oil increased myeloperoxidase activity, which was inhibited by Pemulen® TR2 3% OA (Imax = 71.37 ± 10.97%) and by 0.5% dexamethasone (Imax = 96.31 ± 3.73%). Pemulen® TR2 3% OA also prevented the increase in pro-inflammatory cytokine IL-1β levels induced by croton oil (Imax = 94.18 ± 12.03%), similar to 0.5% dexamethasone (Imax = 87.21 ± 10.58%). Besides, both Pemulen® TR2 3% OA and 0.5% dexamethasone inhibited IL-1β-induced ear oedema with an Imax of 80.58 ± 2.45% and 77.46 ± 1.92%, respectively. OA and dexamethasone anti-inflammatory effects were prevented by 100% and 91.43 ± 5.43%, respectively, after pretreatment with mifepristone. No adverse effects were related to Pemulen® TR2 3% OA administration. ConclusionsOA demonstrated anti-inflammatory efficacy similar to dexamethasone, clinically used to treat skin inflammatory conditions, without presenting adverse effects.

JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation

BackgroundUsing JAK inhibitors to inhibit cytokine signaling is presumed to be a possible means of treating skin inflammatory disorders such as contact dermatitis. ObjectiveTo clarify the action site of JAK inhibitors in skin inflammatory disorders. MethodsWe analyzed the mechanism of action of the JAK inhibitor JTE-052 using murine skin inflammation models, including contact hypersensitivity (CHS) and irritant contact dermatitis. Cells isolated from ear tissue or lymph node (LN) were analyzed by flow cytometry. The amounts of cytokines in the culture medium were measured by ELISA or bead array system. Proliferation of LN cells was evaluated by measurement of tritiated thymidine incorporation. ResultsOral administration of JTE-052 during both sensitization and elicitation phase attenuated CHS, but did not affect croton oil-induced irritant contact dermatitis. JTE-052 potently inhibited T cell proliferation and activation by antigen presentation in vitro, and attenuated skin inflammation in a sensitized-lymphocyte transfer model without suppressing T cell migration. JTE-052 did not affect hapten-induced cutaneous dendritic cell migration into draining lymph nodes or their costimulatory molecule expressions. ConclusionThe JAK inhibitor JTE-052 exerts an inhibitory effect on antigen-specific T cell activation and subsequent inflammation in acquired skin immunity, such as CHS.

Epidermal NLRP10 contributes to contact hypersensitivity responses in mice.

The nucleotide binding and oligomerization domain-like receptor (NLR) protein NLRP10 is highly expressed in the epidermis and contributes to cell-autonomous responses against invasive bacteria. To investigate the role of NLRP10 in inflammatory responses of the skin we analyzed the effect of full-body and keratinocyte-specific depletion of NLRP10 in croton oil-induced irritant contact dermatitis (ICD) and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced contact hypersensitivity (CHS) in mice. Nlrp10(-/-) mice were phenotypically normal and skin repair after wounding was not affected by lack of NLRP10. Similarly, we did not detect a contribution of NLRP10 to the ICD response induced by croton oil. In contrast, Nlrp10(-/-) mice showed significantly reduced inflammation in the DNFB-induced CHS response as compared to control animals. Microscopic analysis revealed significantly reduced numbers of CD4(+) and CD8(+) T cells in the infiltrates of animals lacking NLRP10 expression after CHS challenge. Epidermis-specific deletion of Nlrp10 by keratin-14 promotor driven Cre-recombinase was sufficient to account for this phenotype, although lymphocyte recruitment seemed to be unaltered in animals lacking NLRP10 expression in keratinocytes. Taken together, we provide evidence that NLRP10 contributes to T-cell-mediated inflammatory responses in the skin and highlight a physiological role of NLRP10 in epidermal keratinocytes.

Sex Differences in Opioid-Induced Enhancement of Contact Hypersensitivity

Previous research has demonstrated that, in male rats, the magnitude of contact hypersensitivity (CHS) can be enhanced by morphine treatment. The present experiments test the hypothesis that the mu-opioids morphine, etorphine, and buprenorphine would produce significant sex differences in the magnitude of 2,4-dinitrofluorobenzene-induced CHS. During tests conducted over a 192-h period, morphine, etorphine, and buprenorphine administered before elicitation of CHS on the external surface of the ear (pinna) potentiated the CHS response, and the magnitude of this enhancement was significantly greater in females than males. By contrast, morphine had no effect on croton oil-induced irritant contact dermatitis, indicating that morphine's effects on CHS do not generalize to immunologically nonspecific forms of contact dermatitis. Activation of brain mu-opioid receptors is responsible for the effects of morphine on CHS, because intracerebroventricular treatment with the mu-opioid receptor antagonist beta-funaltrexamine blocked morphine potentiation of CHS in females and males. The sex differences in morphine potentiation of CHS appear to be a result of the gonadal hormonal milieu, because castration enhanced the CHS response following vehicle and morphine treatment, whereas ovariectomy significantly attenuated the enhancement of CHS by morphine. Because ovariectomy had no effect on the CHS response following vehicle treatment, the presence of female gonadal hormones may underlie the sex differences in morphine potentiation of CHS in gonadally intact animals. Overall, these results support an increased sensitivity to the modulatory effects of opioids on the CHS response in females that depends on the interaction between gonadal hormones and the central mu-opioid system.

Studies on the role of leukotrienes in murine allergic and irritant contact dermatitis.

A specific peptidoleukotriene receptor antagonist, Ro 23-3544, was tested for its efficacy in modulating DNFB-induced allergic and croton oil-induced irritant contact dermatitis in mouse ears. Treatment shortly after elicitation of the dermatitis, and for up to 5 days thereafter, was moderately effective in suppressing DNFB-induced ear swelling in a dose-dependent fashion. Daily pre-treatment of the ears for 1 week caused a more marked reduction of DNFB-induced ear swelling during the first 48 h after elicitation. No reduction, but rather an increase in ear swelling was observed with croton oil-induced dermatitis. These results indicate that peptidoleukotrienes play a role in the early stages of elicitation of murine allergic, but not irritant contact dermatitis and that a specific receptor antagonist can only partially reverse the effect of peptidoleukotrienes once the dermatitis is established.