Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 4, Issue 1, 2005

In general, there are two types of immune systems: innate immunity and acquired immunity. The innate immune system provides the first line of defense against many common microorganisms including bacteria and virus. This primitive immune system provides broad but relatively non-specific host defense that lacks the properties of antigenic specificity and immunological memory. In contrast, the acquired immune system is more sophisticated and is mediated by T and B cells, both of which generate their own receptors and specificities through DNA rearrangement, and is observed only in highly organized organisms. This highly sophisticated system has received much more attention and been studied more extensively in the past than the innate immune system. However, innate immunity is very important because of the following two reasons: 1) only innate immunity can respond to infections early on because it takes three to seven days before the initial adaptive immune response takes effect; and 2) recent studies have revealed that the innate immune response is vital to the activation of acquired immunity. For example, innate immune signaling such as Toll-like receptor (TLR) mediated signaling influences T cell activation and differentiation through dendritic cells (DCs) (Scheme 1). DCs are the most important antigen-presenting cells and are involved in the activation of naïve T cells. Upon infection, DCs recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) that are expressed by many pathogens but not by hosts. TLRs in DCs recognize PAMPs. Upon PAMP stimulation, TLRs mostly form homodimers, resulting in a conformational change in their cytoplasmic TLR / IL-1R / plant R (TIR) domain and the subsequent recruitment of an adaptor protein, MyD88. MyD88 associates with TLRs via the TIR domain. MyD88 then recruits downstream IL-1 receptor associated kinase-4 (IRAK-4) via its death domain (DD). Four IRAKs have been identified so far, namely, IRAK-1, IRAK-2, IRAK-M and IRAK-4. Of these, IRAK-4 is the most indispensable to TLR signaling according to knockout mouse studies. The TNF receptor associated factor 6 (TRAF6) is activated, which in turn activates such nuclear transcription factors as NF-kB and AP-1 through the IKK complex and JNK, respectively. NF-kB and AP-1 finally induce the activation of immune response genes, resulting in the production of inflammatory cytokines. These cytokines are involved in the differentiation of naïve T cells. On the other hand, TLR signaling also induces the expression of MHC and costimulatory molecules on the surface of DCs in order to induce clonal expansion and differentiation of the recipient naïve T cells. Naïve T cells finally differentiate into Th1 and Th2 cells that influence macrophage activation and Ag-specific B cell activation, respectively. These T cell responses are classified under the acquired immune system. Scheme 1 shows an example of how the innate immune system is linked to acquired immunity. Recently, it has been recognized that innate immunity is a fundamental and critical system for triggering acquired immunity. Dr. Takeda has summarized TLRs that are specific for innate immune responses, and has discussed adaptor molecules that can bind to TLRs. Our group has summarized IL-1 receptor associated kinases (IRAKs), which are the regulatory kinases of innate immune signaling. We have also discussed how IRAKs, in particular IRAK-4, effect acquired immunity and human disease. On the other hand, Dr. Li has summarized signal transduction in innate immunity by concentrating on a critical TLR negative regulator, SIGIRR. Dr. Fujita's group has given us a more detailed scheme of innate immune signaling by paying attention to the IRF family. Dr. Cheng's group has introduced Rip2, a kinase crucial to both innate and acquired immunity. Dr. Inohara's group has introduced Nod proteins, which are important for innate immunity and apoptosis. Dr. Shibuya's group has summarized DNAM-1, a leukocyte adhesion molecule considered to be a two-sword fencer in innate and adaptive immunity. Dr. Taniguchi's group has summarized NKT cells, which are bridging cells between innate and acquired immunity. The objectives of this review are to: 1) summarize most recent knowledge of innate immunity; and 2) present lines of evidence indicating that innate immunity is indispensable to acquired immunity. This new concept of the innate immune system poses a challenge to the current views on pathogenesis and the treatment of infectious diseases, immune diseases, allergenic diseases, and cancers.

Toll-like receptors (TLRs) recognize specific molecular patterns of pathogenic microorganisms, including bacteria, fungi, protozoa, and virus. Stimulation of TLRs triggers gene expression involved in innate immune response and further instructs development of antigen-specific adaptive immunity. Molecular mechanisms by which TLRs activate innate immunity are now being elucidated through analysis of TLR-mediated signaling pathways. TLR signaling originates from the cytoplasmic Toll / IL-1 receptor (TIR) domain, which is conserved among all TLRs. In addition, recent evidence indicates that TIR domain-containing adaptors, such as MyD88, TRIF, TIRAP, and TRAM, play essential roles in TLR signaling. MyD88 is essential for inflammatory cytokine production via all TLRs, whereas TRIF mediates a MyD88-independent induction of type I IFNs via TLR3 and TLR4. TIRAP is specifically involved in TLR2-, and TLR4- mediated MyD88-dependent pathway, and TRAM acts in the TLR4-mediated TRIF-dependent pathway. Therefore, the specific functions of individual TLRs can be elicited by utilizing different combinations of TIR domain-containing adaptors. These recent progresses have made us aware of the fact that innate immunity possesses a skillful system to detect microbial invasion in the host and trigger appropriate immune responses.

Toll-like receptors (TLRs), interleukin 1 receptor (IL-1R), IL-18 receptor (IL-18R) and plant R are vital to the induction of acute inflammation as well as various adaptive immune responses upon invasion of microorganisms. These receptors share a common cytoplasmic domain called the TIR (TLR / IL-1R / plant R) domain and the signaling cascade involving the TIR domain is conserved from invertebrate to vertebrate. The engagement of TIR domain containing receptors initiates their signaling through several intermediate proteins including serine-threonine kinase IL-1 receptor associated kinases (IRAKs). The IRAK family has four members and the newest member, IRAK-4, is indispensable to the TIR-mediated signaling pathway. The improper regulation of TIR receptor signaling leads to the development of such severe inflammatory diseases as sepsis, asthma, rheumatoid arthritis and even cancer. Therefore, it is very important to determine precisely the implications of TIR signaling in those inflammatory diseases for appropriate medical treatment and drug development. As IRAK-4 is the critical molecule for TIR-mediated signaling, it is a promising therapeutic target for many inflammatory diseases. In this review, we discuss the functions of the IRAK family members with focus on IRAK-4, to seek the possibility of yielding new therapeutic strategies.

Toll-like receptors (TLRs) belong to the Toll-IL-1 receptor superfamily, which is defined by a common intracellular Toll-IL-1 receptor (TIR)-domain. These receptors employ related yet distinct signaling components and downstream pathways, leading to activation of the transcription factors NFkB, ATF and IRF3. Recent studies have also begun to unravel how these pathways are negatively regulated. SIGIRR (also known as TIR8), a member of Toll-IL-1R superfamily that does not activate the transcription factors NFkB, ATF and IRF3, instead negatively modulates responses. Inflammation is enhanced in SIGIRR-null mice as measured by enhanced chemokine induction after IL-1 injection and a reduced threshold for lethal endotoxin challenge. SIGIRR-deficient mice are more susceptible to DSS-induced inflammatory bowel disease. Cells from SIGIRR-null mice show enhanced activation in response to either IL-1 or certain Toll ligands. Therefore, SIGIRR functions as a biologically important modulator of Toll-IL-1R signaling.

Toll like receptors (TLRs) function as signaling receptors for pathogen-derived molecules and provoke innate immune responses, which are preparatory for initiating acquired immunity. Each TLR triggers both common and unique signals, resulting in the activation of a specific set of transcription factors and hence the activation of common and specific target genes. Some members of the Interferon Regulatory Factor (IRF) family of transcription factors are specifically activated by TLR signaling and participate in the critical processes of innate immunity. Recently, a non-TLR receptor that recognizes viral double stranded RNA and participates in the antiviral innate responses was identified.

The Receptor interacting protein-2 (Rip2, also called RICK, CARDIAK) is an intracellular serine-threonine kinase that contains a carboxy-terminal caspase activation and recruitment domain (CARD). The initial biochemical analysis emphasized a role for Rip2 in the activation of nuclear factor-kappaB (NF-kB) and apoptosis when overexpressed. The subsequent generation of mice with a targeted deletion of the gene for Rip2 and the description of a possible target for Rip2 kinase activity has clarified the role of Rip2. Following infectious challenges, the activation of a protective immune response relies on the coordinated interplay of contextual stimulation and inflammatory processes. All mammals must balance the need to combat dangerous pathogens from the destructive potential for mistaking autologous cells or proteins as appropriate targets for response. Rip2 has carved out an evolutionary niche serving as a regulator of inflammatory responses. Rip2 helps to direct or propagate signals towards cell-mediated immune responses and resolution of infection by modifying signals from pathogen recognition receptors (PRRs) such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (Nod) family members of innate immunity, the T cell receptor (TCR) complex of acquired immunity, and cytokine signaling of the interleukin (IL)-1 receptor family and IL-12 signaling pathways. Here we wish to outline the progress made in describing the biological significance of Rip2 and the mode of regulation of this kinase. Further studies considering Rip2 as a target of intervention have the potential to be of great clinical value.

Nod proteins are defined as proteins carrying nucleotide-oligomerization domains (NODs) and are involved in regulation of immune responses and apoptosis. The Nod protein family contains 23 human members including Nod1, Nod2, cryopyrin, Ipaf, Apaf-1 and CIITA, as well as thousands of plant proteins, which are involved in pathogen-specific defense responses. A Nod protein generally contains an amino-terminal domain for binding downstream effector molecules, a central NOD and a carboxyl-terminal ligand recognition domain (LRD). Nod1 and Nod2 are involved in host recognition of small molecules that are components of bacterial peptidoglycan and activate nuclear factor kB (NF-kB) in response to sensing these molecules. This NF-kB activation occurs in a RICK- and IKK-dependent manner. The core ligand structure for Nod2 is muramyl dipeptide, a structural motif common in all bacteria, whereas the ligand for Nod1 is a dipeptide designated as iE-DAP, a motif found in only certain subgroups of bacteria. These molecules and their derivatives mediate host innate responses against bacteria and also function as immunostimulatory adjuvants through induction of cytokine secretion and co-stimulatory molecule expression. Although the mechanism is unknown, genetic and functional defects of Nod proteins are associated with several inflammatory diseases and immunodeficiency. These include susceptibility for Crohn's disease and Blau syndrome (Nod2), three related inflammatory diseases (cryopyrin) and type II bare lymphocyte syndrome (CIITA). Functional analyses of mutant Nod proteins suggest a common molecular basis for these diseases.

The leukocyte adhesion molecule DNAM-1 (CD226) is a member of the immunoglobulin superfamily and constitutively expressed on the majority of CD4+ and CD8+ T lymphocytes, natural killer (NK) cells, monocytes / macrophages, platelets and megakaryocytes and a subset of B lymphocytes. The poliovirus receptor (CD155) and its family member nectin 2 (CD112) have recently been identified as the ligands for DNAM-1. Interaction of DNAM- 1 with the ligands induces NK cell- and CD8+ T cell-mediated cytotoxicity and cytokine secretion. Upon antigen recognition by the T cell receptor, DNAM-1 physically associates with the αLβ2 integrin adhesion molecule LFA-1 and plays an essential role for LFA-1-mediated costimulatory signals for differentiation from naïve CD4+ T cells toward Th1 cells. Moreover, DNAM-1 is involved in macrophage and platelet activation and adhesion to vascular endothelial cells. Thus, DNAM-1 is involved in a variety of hematopoietic cell functions for innate and adaptive immunities.

CDd-restricted NKT cells are a unique subset of lymphocytes bridging innate and acquired immunity and mediating both effector and regulatory functions in immune responses. NKT cells are essential for the protection against pathogens or tumors, and also play a regulatory role in transplantation tolerance and autoimmune disease development. This review focuses on the various functions of NKT cells and discusses fundamental mechanisms in NKT cell biology.

Some medicinal plants, which are known to produce allergic reactions, are also specifically used as antiinflammatory agents. Among the more relevant plants, we report species with cinnamaldehyde, cinnamic alcohol, geraniol, hydroxycitronellal, eugenol and isoeugenol are all potential allergens. In addition, fragrances, which are mixtures of small-molecular-weight compounds, may induce allergic contact dermatitis due to fragrance-specific CD4+ and CD8+ T lymphocytes. Plants from the Asteraceae family used in folk medicine as anti-inflammatories can cause allergic contact dermatitis because of its content in sesquiterpene lactones, which have been reported as the antiinflammatory principles in this species. Species with flavonoids, iridoids, terpenoids and alkaloids have been described as inhibitors of contact dermatitis. Scrophularia auriculata, Poria cocos, Santolina chamaecyparissus, Ranunculus sceleratus and Helichrysum italicum all showed activity in different experimental protocols of contact dermatitis, thus justifying the potential use of these medicinal plants as anti-allergens and inhibitors of contact dermatitis reactions produced by allergens and chemicals. Hydroquinone derivatives such as 1-O-b-glucopyranosyl-2-(3'-hydroxymethyl-3'-methylallyl) hydroquinone and arbutin, flavonoids such as kaempferol, apigenin and genistein, sesquiterpene lactones such as helenalin, diterpenes such as triptonide, triterpenes such as tripterine and bryonolic acid, iridoids such as scrovalentinoside, alkaloids such as indirubin, dehydrocorydaline, magnoflorine hydroxide and phellodendrine acetate, and polysaccharides such as fucoidin have been reported as inhibitors of contact dermatitis reactions.

Allergic disorders are characterized by typical symptoms and an infiltrate of cells, including Th2 lymphocytes, eosinophils and mast cells. Activated mast cell mediators cause the early appearance of symptoms, and cytokines induce a cascade of inflammatory events. Both resident and infiltrating cells are important sources of those mediators and cytokines which maintain and enhance the allergic inflammatory response. The predominant preformed mediator released by mast cells and basophils is histamine, which binds to specific cell receptors to produce its clinical effects. Therapeutic intervention in allergic disease has thus commonly focused on blocking the action of histamine. Ever since Arunlakshana demonstrated, in 1953, the ability of antihistamines to inhibit histamine release by mast cells, numerous studies have been conducted, both in vivo and in vitro , to determine the H1 antihistamines additional properties which contribute to their clinical efficacy in the treatment of allergic disease. It has been reported that some antihistamines can also regulate the expression and / or release of cytokines, chemokines, adhesion molecules, and or / inflammatory mediators. Such properties make these agents important tools for the continuous longterm regulation of both early and late-phase allergic reactions. It appears likely that antihistamines exert these antiinflammatory effects by means of both receptor-dependent and receptor-independent mechanisms. The receptordependent mechanisms seem to involve inhibition of the generation of NF-kB dependent cytokines and adhesion proteins. The latter mechanisms, which require higher drug concentrations, appear to include the release by inflammatory cells of pre-formed mediators, such as histamine and eosinophil proteins as well as eicosanoid generation and oxygen free radicals production. Herein, we review the current state of knowledge of the anti-inflammatory properties of antihistamines and their mechanisms.

Somatostatin binds to five receptors sst1-sst5, belonging to the G-protein coupled receptor super family. So far, only sst2 preferring analogs, presenting also high affinity for sst5 and moderate affinity for sst3, are available for clinical use to treat certain hormonal disorders and tumors (pituitary adenomas and gastroenteropancreatic tumors) with longlasting efficacy and minimal side-effects as observed in patients with acromegaly. Recent strategies based on sequence modifications, such as D-substitutions, deletions, backbone cyclisation technology, novel thiourea scaffolds, along with combinatorial chemistry, lead to the discovery of peptide and non peptide compounds, with either combined affinities for two or more receptor subtypes, or exclusive selectivity for one of them, or a universal profile binding, more stable than the natural peptides. A large field of potential novel drugs has been open. Molecular mechanisms for anti-inflammatory properties of somatostatin and analogs involve anti-secretory, anti-proliferative and anti-angiogenic properties, which may be receptor selective. The great diversity of new analogs and major progress in the understanding of biological activity of somatostatin and receptors support strategies for targeting somatostatin to treat some chronic inflammatory diseases which are still a major cause of disability.