Toll-like receptors (TLRs) are pivotal components of the innate immune response, which is responsible for eradicating invading microorganisms through the induction of inflammatory molecules. These receptors are also involved in responding to harmful endogenous molecules and have crucial roles in the activation of the innate immune system and shaping the adaptive immune response. However, TLR signaling pathways must be tightly regulated because undue TLR stimulation may disrupt the fine balance between pro- and anti-inflammatory responses. Such disruptions may harm the host through the development of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Several studies have investigated the regulatory pathways of TLRs that are essential for modulating proinflammatory responses. These studies reported several pathways and molecules that act individually or in combination to regulate immune responses. In this review, we have summarized recent advancements in the elucidation of the negative regulation of TLR signaling. Moreover, this review covers the modulation of TLR signaling at multiple levels, including adaptor complex destabilization, phosphorylation and ubiquitin-mediated degradation of signal proteins, manipulation of other receptors, and transcriptional regulation. Lastly, synthetic inhibitors have also been briefly discussed to highlight negative regulatory approaches in the treatment of inflammatory diseases.
Animals ; Cytokines/biosynthesis ; Humans ; Ligands ; Models, Immunological ; Signal Transduction/*immunology ; Toll-Like Receptors/antagonists & inhibitors/*metabolism

How is the balance between immune response and immune tolerance dynamically kept in the complicated immune system of human body? To answer this question, many scientists have proposed various models since 1950's. A brief introduction to these models is given in this mini-review, which might reflect the historical process in the development of immunology in the past half century.
Animals ; Clonal Anergy ; Clone Cells ; Humans ; Immune Tolerance ; Immunity ; Models, Immunological

Atherosclerosis is a chronic progressive vascular disease. It starts early in life, has a long asymptomatic phase, and a progression accelerated by various cardiovascular risk factors. The endothelium is an active inner layer of the blood vessel. It generates many factors that regulate vascular tone, the adhesion of circulating blood cells, smooth muscle proliferation, and inflammation, which are the key mechanisms of atherosclerosis and can contribute to the development of cardiovascular events. There is growing evidence that functional impairment of the endothelium is one of the first recognizable signs of development of atherosclerosis and is present long before the occurrence of atherosclerotic cardiovascular disease. Therefore, understanding the endothelium's central role provides not only insights into pathophysiology, but also a possible clinical opportunity to detect early disease, stratify cardiovascular risk, and assess response to treatments. In the present review, we will discuss the clinical implications of endothelial function as well as the therapeutic issues for endothelial dysfunction in cardiovascular disease as primary and secondary endothelial therapy.
Animals ; Atherosclerosis/*drug therapy/*immunology ; Cytokines/*immunology ; Endothelium, Vascular/*immunology ; Humans ; *Models, Immunological ; Muscle, Smooth, Vascular/*immunology

This report gives a better emphasis on the role of targeted effectors (e.g. a combination of 5-FC with CD-NSPCs as compared to the application of NSPCs alone) and how such delivery of pro-drug activating enzymes and other tumor-killing substances may overcome melanocytic defence system, interact with and promote the host defence and immune response modulations not only in melanoma but, potentially, in other highly-metastatic cancers.
Brain Neoplasms ; immunology ; surgery ; Humans ; Immunity, Innate ; immunology ; Melanoma ; immunology ; secondary ; surgery ; Models, Immunological ; Stem Cell Transplantation ; methods

Pattern recognition receptors (PRRs) in innate immune cells play a pivotal role in the first line of host defense system. PRRs recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to initiate and regulate innate and adaptive immune responses. PRRs include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs), which have their own features in ligand recognition and cellular location. Activated PRRs deliver signals to adaptor molecules (MyD88, TRIF, MAL/TIRAP, TRAM, IPS-1) which act as important messengers to activate downstream kinases (IKK complex, MAPKs, TBK1, RIP-1) and transcription factors (NF-kappaB, AP-1, IRF3), which produce effecter molecules including cytokines, chemokines, inflammatory enzymes, and type I interferones. Since excessive PRR activation is closely linked to the development of chronic inflammatory diseases, the role of intrinsic and extrinsic regulators in the prevention of over- or unnecessary activation of PRRs has been widely studied. Intracellular regulators include MyD88s, SOCS1, TOLLIP, A20, and CYLD. Extrinsic regulators have also been identified with their molecular targets in PRR signaling pathways. TLR dimerization has been suggested as an inhibitory target for small molecules such as curcumin, cinnamaldehyde, and sulforaphane. TBK1 kinase can be a target for certain flavonoids such as EGCG, luteolin, quercetin, chrysin, and eriodictyol to regulate TRIF-dependent TLR pathways. This review focuses on the features of PRR signaling pathways and the therapeutic targets of intrinsic and extrinsic regulators in order to provide beneficial strategies for controlling the activity of PRRs and the related inflammatory diseases and immune disorders.
Adaptive Immunity ; Gene Expression Regulation ; Humans ; *Immunity, Innate ; *Models, Immunological ; Receptors, Pattern Recognition/genetics/metabolism/*physiology ; Signal Transduction ; Toll-Like Receptors/genetics/metabolism/physiology ; Transcription Factors/physiology

With growing accounts of inflammatory diseases such as sepsis, greater understanding the immune system and the mechanisms of cellular immunity have become primary objectives in immunology studies. High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is implicated in various aspects of the innate immune system as a damage-associated molecular pattern molecule and a late mediator of inflammation, as well as in principal cellular processes, such as autophagy and apoptosis. HMGB1 functions in the nucleus as a DNA chaperone; however, it exhibits cytokine-like activity when secreted by injurious or infectious stimuli. Extracellular HMGB1 acts through specific receptors to promote activation of the NF-kappaB signaling pathway, leading to production of cytokines and chemokines. These findings further implicate HMGB1 in lethal inflammatory diseases as a crucial regulator of inflammatory, injurious, and infectious responses. In this paper, we summarize the role of HMGB1 in inflammatory and non-inflammatory states and assess potential therapeutic approaches targeting HMGB1 in inflammatory diseases.
Amino Acid Sequence ; HMGB1 Protein/chemistry/metabolism/*physiology ; Humans ; Immunity, Innate/*physiology ; *Models, Immunological ; Molecular Sequence Data ; Protein Structure, Tertiary ; Signal Transduction

The importance of innate immunity in host defense is becoming clear after discovery of innate immune receptors such as Toll-like receptor or Nod-like receptor. Innate immune system plays an important role in diverse pathological situations such as autoimmune diseases. Role of innate immunity in the pathogenesis of metabolic disorders such as type 2 diabetes, metabolic syndrome or atherosclerosis that has not been previously considered as inflammatory disorders, is also being appreciated. Here, the role of innate immunity in the development of type 1 diabetes, a classical organ-specific autoimmune disease, and type 2 diabetes will be discussed, focusing on the role of specific innate immune receptors involved in these disease processes.
Animals ; Cytokines/*immunology ; Diabetes Mellitus, Type 1/*immunology ; Diabetes Mellitus, Type 2/*immunology ; Humans ; Immunity, Innate/*immunology ; Inflammasomes/*immunology ; *Models, Immunological ; Pancreas/immunology

IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway-hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-gamma-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-gamma over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-gamma-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-gamma expression were impaired in allergen-challenged IL-12Rbeta2- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-4Ralpha-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-gamma. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-gamma axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.
Allergens/immunology ; Animals ; Asthma/complications/*immunology/pathology/physiopathology ; Bronchial Hyperreactivity/complications/immunology/pathology ; Disease Models, Animal ; Interferon-gamma/*immunology ; Interleukin-12/*immunology ; Interleukin-12 Receptor beta 2 Subunit/metabolism ; Interleukin-13/deficiency/*immunology ; Interleukin-4/deficiency ; Methacholine Chloride ; Mice ; Mice, Transgenic ; Models, Immunological ; Organ Specificity ; Pneumonia/complications/immunology/pathology ; Receptors, Cell Surface/metabolism ; STAT4 Transcription Factor/*metabolism ; Signal Transduction/*immunology ; Th2 Cells/*immunology