Contribution of IL-18 to atopic-dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disease of unknown etiology. Cutaneous infection with microbes such asMajor features of AD are pruritus, chronic relapsing course, and genetic predisposition (1-3). AD is divided into two types: (i) AD associated with IgE-mediated responses, affecting 70-80% of patients and termed ''extrinsic AD,'' and (ii) AD without IgEmediated responses, affecting 20-30% of patients and termed ''intrinsic AD.'' Patients with extrinsic AD show preferential deviation toward T helper type 2 (Th2) responses, together with accumulation of Th2 chemokines such as CCL17 (thymus-and activation-regulated chemokine) and CCL22 (monocyte-derived chemokine) in the cutaneous lesions (1, 2). However, recent clinical studies have revealed that the immunological aspects of the skin lesions are quite different among the clinical stages of AD (1-3). Nonetheless, the immunopathological bases for intrinsic AD are still unknown.Recently, we showed that transgenic mice that oversecrete IL-18 from their epidermal cells spontaneously develop AD-like dermatitis under specific pathogen-free (SPF) conditions, and that the deletion of il18, but not stat6, which encodes a signaling molecule necessary for Th2 and IgE responses, protects against the development of AD (4, 5). This finding suggests that excessive cutaneous IL-18 release is a causative factor for intrinsic-type AD. Recent clinical studies have revealed that IL-18 production levels closely parallel disease severity (6-8). Therefore, it is important to clarify whether, and how, endogenous IL-18 contributes to the development of AD when skin is exposed to natural infectious agents.Although it is well documented that cutaneous infection with Staphylococcus aureus exacerbates clinical AD (1, 3), the underlying mechanism is not fully understood. Recently, we demonstrated that protein A (SpA), a surface molecule and virulent factor of S. aureus (9), stimulates mouse epidermal cells to secrete IL-18 (10). However, cutaneous application of SpA alone did not induce major skin alterations in C57BL͞6 mice, despite the fact that it produced elevated serum levels of 10). This outcome led us to assume that additional factors are required for the development of AD. Because skin cleansing with detergent aggravates clinical AD (1, 11), skin barrier destruction seems to be a second important factor in AD development. Inasmuch as NC͞Nga mice, which have a genetically impaired skin barrier due to reduced ceramide production (12), frequently develop AD-like dermatitis after exposure to mites (13-15), we assumed that genetic skin barrier dysfunction was a third prerequisite for the development of AD. Here, we generated an intrinsic AD mouse model by daily application of SpA, after destruction of the skin barrier with a subclinical dose of SDS, a detergent (16). Neutralizing anti-IL-18 Abs could completely protect against SDS͞SpA-induced AD. Furthermore, il18 Ϫ/Ϫ BALB͞c mice evaded development of AD under SDS͞SpA challenge. Our present results clearly demonstrate th...

T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-γ and IL-13 production

“…We previously reported that mice receiving memory Th1 cells develop AHR and airway inflammation after intranasal administration of OVA and IL-18 (22). Th1 cells produce IFN-␥, IL-9, IL-13, granulocyte-macrophage colony-stimulating factor, and chemokines in response to Ag, IL-2, and IL-18 in vitro (22,25). Among the cytokines produced, IL-13 is most bronchogenic and participates in AHR (7)(8)(9)(10)(11)(12)(13).…”

“…However, our previous studies have clearly demonstrated that IL-18 disrupts the biologically reciprocal actions of Th1 and Th2 cells in mice (22,24,25). We showed that OVA-specific monoclonal Th1 cells, which we developed in vitro, have the potential to produce Th1 cytokine (IFN-␥) and Th2 cytokine (IL-9, IL-13) as well as chemokines (e.g., RANTES and macrophage inflammatory protein 1␣) in response to Ag, IL-2, and IL-18 in vitro (22,25). Thus, Ag-and IL-18-stimulated Th1 cells produce a similar spectrum of cytokines and chemokines that are produced by activated mast cells.…”

“…Human Th1 cells also produce Th1 and Th2 cytokines and IL-8 in response to anti-CD3 plus IL-18 (24). Recently, we demonstrated Th1 cells induce intrinsic atopic dermatitis by production of Th1 and Th2 cytokines and chemokines (25). Thus, IL-18 has added its new function to its growing functional list (26)(27)(28)(29).…”

“…Thus, IL-18 has added its new function to its growing functional list (26)(27)(28)(29). Based on this unique function of Ag-plus IL-18-stimulated Th1 cells, we proposed to designate them as ''super Th1 cells'' (25). It is important to determine the mechanism by which super Th1 cells induce bronchial asthma by production of both Th1 and Th2 cytokines.…”

Kadar Interleukin-18 pada Kultur Limfosit Penderita Dermatitis Atopik yang Distimulasi Staphylococcal Enterotoxin B (SEB)

“…Kadar IL-18 meningkat pada DA dan diduga berhubungan dengan kolonisasi S. aureus. 3 Tujuan penelitian ini adalah mengetahui peningkatan kadar sitokin IL-18 pada kultur limfosit pasien DA yang distimulus dengan Staphylococcal enterotoxin B (SEB).…”