Kazuhiko Arima

IL-4 and IL-13: Their Pathological Roles in Allergic Diseases and their Potential in Developing New Therapies

The incidence of allergic diseases has dramatically increased in recent decades, and it is socially and medically important to establish more useful strategies to overcome allergic disorders. Various kinds of drugs are utilized for allergic patients; however, some cases are unresponsive to these drugs and in others there are undesired adverse effects. On the other hand, a substantial body of evidence has accumulated pointing to the pivotal role of Th2-cytokines, interleukin (IL)-4, and IL-13, in the pathogenesis of bronchial asthma. The evidence is categorized as (1) expression of these cytokines in the bronchial lesions, (2) genetic association of the signaling molecules of these cytokines, (3) analyses of mouse models. In addition, the molecular mechanism of the signal transduction of these cytokines has also been well characterized. Based on such information, IL-4 and IL-13 have emerged as promising means of improving allergic states, and several IL-4/IL-13 antagonists have been developed, among which soluble IL-4 receptor is now in human trials. Identifying the structure of the IL-13 variant and of the IL-4/IL-13-inducing genes would be of great use. It is expected that in the near future, several drugs will emerge based on these strategies, which will give us wider choice in treating patients, depending on the pathogenesis of the diseases.

The squamous cell carcinoma antigen 2 inhibits the cysteine proteinase activity of a major mite allergen, Der p 1

The squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 belong to the ovalbumin-serpin family. Although SCCA1 and SCCA2 are closely homologous, these two molecules have distinct properties; SCCA1 inhibits cysteine proteinases such as cathepsin K, L, and S, whereas SCCA2 inhibits serine proteinases such as cathepsin G and human mast cell chymase. Although several intrinsic target proteinases for SCCA1 and SCCA2 have been found, the biological roles of SCCA1 and SCCA2 remain unknown. A mite allergen, Der p 1, is one of the most immunodominant allergens and also acts as a cysteine proteinase probably involved in the pathogenesis of allergic diseases. We have recently shown that both SCCA1 and SCCA2 are induced by two related Th2-type cytokines, IL-4 and IL-13, in bronchial epithelial cells and that SCCA expression is augmented in bronchial asthma patients. In this study, we explored the possibility that SCCA proteins target Der p 1, and it turned out that SCCA2, but not SCCA1, inhibited the catalytic activities of Der p 1. We furthermore analyzed the inhibitory mechanism of SCCA2 on Der p 1. SCCA2 contributed the suicide substrate-like mechanism without formation of a covalent complex, causing irreversible impairment of the catalytic activity of Der p 1, as SCCA1 does on papain. In addition, resistance to cleavage by Der p 1 also contributed to the inhibitory mechanism of SCCA2. These results suggest that SCCA2 acts as a cross-class serpin targeting an extrinsic cysteine proteinase derived from house dust mites and that it may have a protective role against biological reactions caused by mites.

IL-13: A Promising Therapeutic Target for Bronchial Asthma

The incidence of allergic diseases has dramatically increased in recent decades, especially in urban and industrialized areas. It is important socially as well as medically to establish more useful strategies to overcome allergic disorders. Bronchial asthma is a complex disease characterized by airway inflammation involving a Th2-cytokine, interleukin (IL)-13. A substantial body of evidence has accumulated pointing to the pivotal role of IL-13 in the pathogenesis of bronchial asthma, based on mainly analyses of mouse models. In addition to such analyses, the high expression of IL-13 in lesions and genetic association of several genes coding IL-13 signaling molecules with bronchial asthma have raised the possibility that IL-13 plays a pivotal role in the onset or exacerbation of human bronchial asthma. Therefore, IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic agent for bronchial asthma. In this article, we describe how IL-13 is involved in the pathogenesis of bronchial asthma and then how therapeutic agents to block IL-13 signals are developed for bronchial asthma.

Recent advances in understanding how interleukin 13 signals are involved in the pathogenesis of bronchial asthma.

The prevalence of allergic disease has dramatically increased in recent decades, especially in urban and industrialized areas. Allergic diseases are disorders of the immune system, the results of complex interactions among various genetic and environmental factors. Among them, the important role of interleukin 13 (IL-13), a Th2-type cytokine, has recently emerged in the pathogenesis of bronchial asthma. Based on studies using mice, great attention has been paid to the direct effects of IL-13 on bronchial tissues. In this review, we describe recent advances in understanding the signal transduction mechanism of IL-13, the involvement of IL-13 signal-related genes as genetic factors in the pathogenesis of bronchial asthma, and the expression of IL-13 receptor on bronchial tissues. We describe potential strategies for targeting IL-13 signals to improve allergic states.

The Roles of Th2-Type Cytokines in the Pathogenesis of Atopic Dermatitis

Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic inflammatory skin disease (1, 2). Analyses of the cytokine expression profile in skin lesions of AD patients show that the Th2-type immune response is dominant in AD inflammation (3, 4). Interleukin-4 (IL4), IL-5, and IL-13 are signature cytokines of the Th2-type immune response. Expression of IL-4 and IL-13 is significantly high in acute lesions of AD skin; however, it is downregulated in chronic lesions. In contrast, expression of IL-5 is more elevated in chronic lesions than in acute lesions. High expression of IL-4, IL-5, and IL-13 in AD skins leads to high serum levels of IgE and eosinophilia, typical clinical features of AD. In addition to IL-5, expression of interferon-┛ (IFN-┛) and IL-12 is elevated in chronic skin lesions of AD. IFN-┛ and IL-12 are signature cytokines of Th1-type immune response. It has remained unclear why this immune milieu change occurs. Based on observations of the predominant Th2-type immune responses in AD patients, many studies using model mice or involving genetic association have been performed to investigate the role played by Th2-type cytokines in the pathogenesis of AD. It is hoped that Th2-type cytokines will prove to be good targets to develop therapeutic agents for AD. In this chapter, we focus on these topics; we do not review the details of the structures, the signal pathways, or the biological functions of these Th2-type cytokines. Please refer to other articles regarding with these subjects (5-10).

Palladium A-frame complexes containing carboxylato ligands. Synthesis of [Pd2(O2CR)2{μ-C2(CO2Me)2}(μ-Ph2PCH2SCH2Ph)2] and NMR evidence of the enantiotopic face in the side-by-side complex [Pd2Cl12(μ-Ph2PCH2SCH2Ph)2]

Abstract The A-frame complex [Pd 2 Cl 2 {μ;-C 2 (CO 2 Me) 2 }(μ-Ph 2 PCH 2 SCH 2 Ph) 2 ], obtained by the reaction between the side-by-side complex [Pd 2 Cl 2 (μ-Ph 2 PCH 2 SCH 2 Ph) 2 ] ( 1 ) and dimethyl acetylenedicarboxylate, reacts with silver acetate and silver benzoate to give [Pd 2 (O 2 CR) 2 {μ-C 2 (CO 2 Me) 2 }(μ-Ph 2 PCH 2 SCH 2 Ph) 2 ]·3H 2 O [R = Me ( 3 ), Ph ( 4 )]. Similar reactions with silver salts of ( S )- and racemic-2-phenylpropionic acid afford [Pd 2 (O 2 CHMePh) 2 {μ-C 2 (CO 2 Me) 2 }(μ-Ph 2 PCH 2 SCH 2 Ph) 2 ] [( S )- ( 5 ), racemic- ( 6 )]. The NMR spectra of 5 and 6 show diastereoisomeric signal splitting, elucidating the presence of the enantiotopic face in 1 .