Editorial [Hot Topic: Toll-Like Receptors and Innate Immunity: Potential Drug Targets for Treatment of Infectious, Inflammatory, and Autoimmune Diseases (Executive Editor: Emilio Jirillo)]

In higher vertebrates and in mammals Toll- like receptors (TLRs) represent a bridge between innate and adaptive immunity. In this respect, a number of recent studies have led to the discovery of various TLRs in mice and in men, as well as to the characterization of structure and function of these receptors. In virtue of TLR ability to trigger a cascade of inflammatory and regulatory events, they are currently investigated as specific targets for novel drugs potentially useful in the treatment of various infectious and autoimmune diseases. On these grounds, the present issue of Current Pharmaceutical Design, entitled: "Toll-like receptors and innate immunity: Potential drug targets for treatment of infectious, inflammatory, and autoimmune diseases", will point out the main aspects of biology, function and potential drug targeting of TLRs. The in silico investigation of the phylogenesis of immune receptors will be described by Panaro and associates [1], demonstrating how some receptors are relatively conserved from insects to mammals. Hoebe and associates [2] and Ishi and associates [3] will provide basic information on the structure-function of the broad spectrum of TLRs, also emphasizing novel avenues for future immunotherapy. Butchar and associates [4] will review TLR4 activation by endotoxin with special reference to the regulatory mechanisms of TLR4 signaling. Recognition of beta-glucan, a major component of the fungal cell wall, will be described by Muta [5], as an example of the phylogenesis of innate immunity. Takada and Uehara [6] will consider another bacterial component, peptidoglycan, for its capacity to enhance TLRmediated responses via the NOD pathway. In two companion papers de la Barrera and associates [7] and Lorenz [8] will describe the involvement of TLRs in infectious diseases, even including bacterial infections with special emphasis on novel therapeutic strategies. Netea and associates [9] will review the mechanisms of TLR activation by fungi and potential therapeutic approaches. Nochi and Kiyono [10] and Ishihara and associates [11] will provide information on the innate mucosal immune system and on TLR-drug targeting in gastrointestinal inflammatory diseases. Stoll and associates [12] will review the involvement of endotoxin and TLR4 in vascular inflammation and potential therapeutic targets. In three consecutive papers Amati and associates [13], Pepe and associates [14] and Pepe and associates [15] will describe the TLR-mediated activation of dendritic cells, their involvement in Leishmanmia infantum and Candida albicans infections and novel protocols of TLR drug targeting. Finally, Kumazawa and associates [16] will illustrate the effects of flavonoids as therapeutic agents able to block TLR-mediated pathways leading to production of proinflammatory cytokines. References [1] Panaro, MA, Acquafredda A, Sisto M, Lisi S, Saccia M, Mitolo V. Evolution of a "conserved" amino acid sequence: a model study of an in silico investigation of the phylogenesis of some immune receptors. Curr Pharm Design 2006; 12(32): 4091-4121. [2] Hoebe K, Jiang Z, Georgel P, Tabeta K, Janssen E, Du X, Beutler B. TLR signaling pathways: opportunities for activation and blockade in pursuit of therapy. Curr Pharm Design 2006; 12(32): 4123-4134. [3] Ishi KJ, Uematsu S, Akira S. "Toll" gates for future immunotherapy. Curr Pharm Design 2006; 12(32): 4135- 4142. [4] Butchar JP, Parsa KVL, Marsh CB, Tridandapani, S. Negative regulators of Toll-like receptor 4-mediated macrophage inflammatory response. Curr Pharm Design 2006; 12(32): 4143-4153. [5] Muta T. Molecular basis for invertebrate innate immune recognition of (1-3)-b-D-glucan as a pathogen - associated molecular pattern. Curr Pharm Design 2006; 12(32): 4155-4161. [6] Takada H, Uehara A. Enhancement of TLR-mediated innate immune responses by peptidoglycans through NOD signaling. Curr Pharm Design 2006; 12(32): 4163-4172. [7] de la Barrera S, Aleman M, Sasiain M del C. Toll-like receptors in human infectious diseases. Curr Pharm Design 2006; 12(32): 4173-4184. [8] Lorenz E. TLR2 and TLR4 expression during bacterial infections. Curr Pharm Design 2006; 12(32): 4185- 4193. [9] Netea MG, Ferwerda G, van der Graaf CAA, Van der Meer JWM, Kullberg BJ. Recognition of fungal pathogens by Toll -like receptors. Curr Pharm Design 2006; 12(32): 4195-4201. [10] Nochi T, Kiyono H. Innate immunity in the mucosal immune system. Curr Pharm Design 2006; 12(32): 4203-4213. [11] Ishihara S, Rumi MAK, Ortega-Cava C-F, Kazumori H, Kadowaki Y, Ishimura N, Kinoshita Y. Therapeutic targeting of Toll-llike receptors in gastrointestinal inflammation. Curr Pharm Design 2006; 12(32): 4215- 4228. [12] Stoll LL, Denning GM, Weintraub NL. Endotoxin, TLR4 signaling, and vascular inflammation: potential therapeutic targets in cardiovascular disease. Curr Pharm Design 2006; 12(32): 4229-4245....