Zeytun Ahmet, Chaudhary Anu, Pardington Paige, Cary R, Gupta Goutam
Biosciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545-0001, USA.
Crit Rev Immunol. 2010;30(1):53-67. doi: 10.1615/critrevimmunol.v30.i1.40.
Recognition of the pathogen-associated molecular pattern (PAMP) by host Toll-like receptors (TLR) is an important component of the innate immune response for countering against invading viruses, bacteria, and fungi. Upon PAMP recognition, the TLR induces intracellular signaling cascades that involve adapter, signalosome, and transcription factor complexes and result in the production of both pro- and anti-inflammatory cytokines and chemokines. An inflammatory response for a short duration can be beneficial because it helps to clear the infectious agent. However, prolonged inflammation can be detrimental because it may cause host toxicity and tissue damage. Indeed, excessive production of inflammatory cytokines and chemokines via TLR pathways is often associated with many inflammatory and autoimmune diseases. Therefore, fine control of inflammation in the TLR pathway is highly desirable for effective host defense. In this article, we review intrinsic control mechanisms that include a balance between pro-inflammatory and anti-inflammatory cytokines and chemokines, production of host effectors, and regulation at the level of adapter, signalosome, and transcription factor complexes in the TLR pathways. We also discuss how understanding of the TLR signaling steps leads to the development of small-molecule drugs that can interfere with the formation of active adapter, signalosome, and adapter complexes.
宿主Toll样受体（TLR）对病原体相关分子模式（PAMP）的识别是先天免疫反应的重要组成部分，用于对抗入侵的病毒、细菌和真菌。识别PAMP后，TLR会诱导细胞内信号级联反应，其中涉及衔接蛋白、信号体和转录因子复合物，并导致促炎和抗炎细胞因子及趋化因子的产生。短时间的炎症反应可能是有益的，因为它有助于清除感染因子。然而，长期炎症可能是有害的，因为它可能导致宿主毒性和组织损伤。事实上，通过TLR途径过度产生炎症细胞因子和趋化因子通常与许多炎症和自身免疫性疾病有关。因此，为了有效地进行宿主防御，非常需要对TLR途径中的炎症进行精细控制。在本文中，我们综述了内在控制机制，包括促炎和抗炎细胞因子及趋化因子之间的平衡、宿主效应器的产生以及TLR途径中衔接蛋白、信号体和转录因子复合物水平的调节。我们还讨论了对TLR信号传导步骤的理解如何导致能够干扰活性衔接蛋白、信号体和衔接蛋白复合物形成的小分子药物的开发。
