Sericin improves memory and sociability impairments evoked by transient global cerebral ischemia through suppression of hippocampal oxidative stress, inflammation, and apoptosis.

Sericin (Ser) is a natural neuroactive macromolecule with diverse pharmacological properties, and our previous findings have shown its neuroprotective potentials. This study aimed to investigate the therapeutic potential of Ser on cognitive dysfunction induced by transient global cerebral ischemia/reperfusion (tGI/R) and its mechanism of action. The tGI/R was induced in BALB/c mice by bilateral occlusion of the common carotid arteries for two 5 min followed by a 10-min reperfusion period. After 24 h, mice were treated with normal saline or different doses of Ser (100, 200, and 300 mg/kg) for 10 days. Cognitive performances were assessed using the Barnes maze and social interaction tasks. Oxidative stress markers including superoxide dismutase (SOD), glutathione peroxidase (GPx), total antioxidant capacity (TAC), and malondialdehyde (MDA) as well as pro-inflammatory cytokines (interleukin (IL)-6 and tumor necrosis factor-alpha) and anti-inflammatory cytokine (IL-10) were assessed in the hippocampus. Markers of apoptosis (pro- and cleaved caspase-9 and 3, Bax, and Bcl-2) were assessed by Western blotting. Besides, transferase-mediated dUTP nick end-labeling assay was used to detect apoptotic cell death. We show here that Ser administration improved tGI/R-induced cognitive deficits, enhanced the activity of SOD and GPx, increased TAC levels, while reduced MDA levels. Notably, Ser decreased neuronal apoptotic cell death in the hippocampal dentate gyrus (DG) region, accompanied by suppression of neuroinflammation, downregulation of pro-apoptotic proteins (caspase-9, caspases-3, and Bax), and upregulation of anti-apoptotic protein, Bcl-2. Taken together, Ser administration protected hippocampal neurons from apoptotic cell death by impeding oxidative stress and inflammatory responses and, in turn, improved cognitive function in the tGI/R mice.

Cancer immunotherapy focusing on the role of interleukins: A comprehensive and updated study.

Cytokines bind to specific receptors on target cells to activate intracellular signaling pathways that control diverse cellular functions, such as proliferation, differentiation, migration, and death. They are essential for the growth, activation, and operation of immune cells and the control of immunological reactions to pathogens, cancer cells, and other dangers. Based on their structural and functional properties, cytokines can be roughly categorized into different families, such as the tumor necrosis factor (TNF) family, interleukins, interferons, and chemokines. Leukocytes produce interleukins, a class of cytokines that have essential functions in coordinating and communicating with immune cells. Cancer, inflammation, and autoimmunity are immune-related disorders brought on by dysregulation of cytokine production or signaling. Understanding cytokines' biology to create novel diagnostic, prognostic, and therapeutic methods for various immune-related illnesses is crucial. Different immune cells, including T cells, B cells, macrophages, and dendritic cells, and other cells in the body, including epithelial cells and fibroblasts, generate and secrete interleukins. The present study's main aim is to fully understand interleukins' roles in cancer development and identify new therapeutic targets and strategies for cancer treatment.

Regulatory effect of sericin protein in inflammatory pathways; A comprehensive review.

Sericin protein is a type of protein derived from silk cocoons. Sericin hydrogen bonds cause adhesion to the silk cocoon. This substance contains a large amount of serine amino acids in its structure. At first, the medicinal properties of this substance were unknown, but today many properties have been discovered for this substance. The unique properties of this substance have made it widely used in the pharmaceutical and cosmetic industries. The applications of Sericin in pharmacy are as follows. Sericin is used to repair wounds by producing collagen. Other uses for the drug include anti-diabetic, anti-cholesterol, metabolic modulator, anti-tumor, heart protection, antioxidant, antibacterial, wound healing, cell proliferation, UV protection, freezing, and skin moisturizing. The physicochemical properties of Sericin have attracted the attention of pharmacists and their widespread use in the production of drugs and treatment of diseases. One of the critical and unique properties of Sericin is its anti-inflammatory property. In this article, this property of Sericin is discussed in detail, and according to the experiments performed by pharmacists, this substance has shown a significant effect in eliminating inflammation. This study aimed to evaluate the impact of Sericin protein in relieving inflammation.

The molecular and clinical significance of the Tie/angiopoietin system in leukemia.

BACKGROUND: Angiogenesis and factors affecting it are one of the most critical elements in vascular proliferation. Although they are essential in generating new vessels, their potential to generate solid tumors is accepted as a pathological condition. Leukemia can be an appropriate example of this condition. AIM: This study aims to evaluate the Tie/angiopoietin system effect in Leukemia. METHODS: Leukemia is a pathological condition in which the uncontrolled proliferation of abnormal cells occurs in the bone marrow or lymphatic system. RESULTS: Based on severity and speed of development, many different types of Leukemia have been discovered through years of studying. Acute lymphocytic Leukemia (ALL), acute myeloid Leukemia (AML), chronic lymphocytic Leukemia (CLL), and chronic myeloid Leukemia (CML) are the four main types of Leukemia. CONCLUSION: Leukemia's function, effects, and medication have been a great concern over the years. Angiogenic factors such as angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), angiopoietin-4 (Ang4), a combination of them and their receptors and their effect on Leukemia are the main purposes discussed in this article.

CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro.

Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune responses. Therefore, the main challenge is to overcome inhibitory immune checkpoint molecules and provoke efficient T-cell responses to antigens specifically expressed by cancerous cells. Among the inhibitory immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression on DCs diminishes their maturation and antigen presentation capability. Accordingly, we hypothesized that the expression of CTLA-4 on DCs inhibits the T cell-mediated anti-tumoral responses generated following the presentation of tumor antigens by DCs to T lymphocytes. In this study, we loaded colorectal cancer (CRC) cell lysate on DCs and inhibited the expression of CTLA-4 by small interfering RNA (siRNA) in them to investigate the DCs' functional and phenotypical features, and T-cell mediated responses following DC/T cell co-culture. Our results demonstrated that blockade of CTLA-4 could promote stimulatory properties of DCs. In addition, CTLA-4 silenced CRC cell lysate-loaded DCs compared to the DCs without CTLA-4 silencing resulted in augmented T cell proliferation and cytokine production, i.e., IFN-γ and IL-4. Taken together, our findings suggest CTLA-4 silenced CRC cell lysate-loaded DCs as a promising therapeutic approach however further studies are needed before this strategy can be used in clinical practice.

Dendritic cell-based cancer immunotherapy in the era of immune checkpoint inhibitors: From bench to bedside.

Dendritic cells (DCs) can present tumoral antigens to T-cells and stimulate T-cell-mediated anti-tumoral immune responses. In addition to uptaking, processing, and presenting tumoral antigens to T-cells, co-stimulatory signals have to be established between DCs with T-cells to develop anti-tumoral immune responses. However, most of the tumor-infiltrated immune cells are immunosuppressive in the tumor microenvironment (TME), paving the way for immune evasion of tumor cells. This immunosuppressive TME has also been implicated in suppressing the DC-mediated anti-tumoral immune responses, as well. Various factors, i.e., immunoregulatory cells, metabolic factors, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules, have been implicated in developing the immunosuppressive TME. Herein, we aimed to review the biology of DCs in developing T-cell-mediated anti-tumoral immune responses, the significance of immunoregulatory cells in the TME, metabolic barriers contributing to DCs dysfunction in the TME, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules in DC-based cell therapy outcomes. With reviewing the ongoing clinical trials, we also proposed a novel therapeutic strategy to increase the efficacy of DC-based cell therapy. Indeed, the combination of DC-based cell therapy with monoclonal antibodies against novel immune checkpoint molecules can be a promising strategy to increase the response rate of patients with cancers.

Potential anti-inflammatory effect of anti-HMGB1 in animal models of ICH by downregulating the TLR4 signaling pathway and regulating the inflammatory cytokines along with increasing HO1 and NRF2.

Intracerebral hemorrhage (ICH) is a severe clinical problem without effective treatment; the leading cause is neuroinflammation. High-mobility group box one protein (HMGB1) is an abundant protein in the cell nucleus of most mammalian cells, which exerts its function by binding to chromatin. The present study focused on the therapeutic effect of anti-HMGB1 on ICH via the downregulation of inflammatory pathways. The ICH mice models were created by collagenase IV injection in the striatum of mice. Then, mice were received different medications and divided into three groups: anti-HMGB1, anti-Toll-like receptor 4 (TLR4), and non-treated ICH groups. Cerebrospinal fluid (CSF) was obtained, and ELISA was carried out to determine the levels of inflammatory agents. Microglial cells were isolated from the cerebral hemispheres, and then Real-Time PCR and western blot were performed. The results showed that the anti-inflammatory effects of anti-HMGB1 were tremendous than anti-TLR4. Overall, the results showed that anti-HMGB1 had a more reducer effect on pro-inflammatory cytokines release (****P < 0.0001) and expression (****P < 0.0001) than anti-TLR4 when compared with the control group. It was also determined that anti-HMGB1 increased heme-oxygenase-1 (HO1) and nuclear factor erythroid-derived factor 2-related factor 2 (NRF2) (****P < 0.0001) expression in comparison with the control group while it was not significant for anti-TLR4 (CLI-095). The present study suggested that anti-HMGB1 serves as a potential anti-inflammatory molecule via reducing TLR4-related signaling pathways, pro-inflammatory cytokines production, and increasing the production of the anti-inflammatory cytokine along with heme-oxygenase-1 HO1 and NRF2 increment.

miR-193a-5p as a promising therapeutic candidate in colorectal cancer by reducing 5-FU and Oxaliplatin chemoresistance by targeting CXCR4.

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide. The role of microRNAs (miRNAs/miRs) as small (19-25 nucleotides in length) non-coding RNA molecules that modify gene expression has been shown in several types of cancer. 5-Fluorouracil (5-FU) and oxaliplatin (Ox) are two common chemotherapeutic agents used to treat cancer. The present study aimed to evaluate the expression levels of miR-193a-5p in CRC, and its effect on the C-X-C Motif Chemokine Receptor 4 (CXCR4) target gene alone and in combination with chemotherapeutic drugs, to determine its possible role in chemoresistance. CRC tissues and adjacent non-cancerous tissue were obtained from 67 patients who had undergone surgery to determine the expression levels of miR-193a-5p and CXCR4. Subsequently, qPCR and Western blotting were performed to determine the effect of miR-193a-5p and chemotherapy drugs on CXCR4. َAlso, MTT assay, and flow cytometry was performed to determine their role in cell viability and apoptosis. Besides, the relationship between miR-193a-5p and CXCR4 with patients' clinical features was investigated. The results of the present study showed that miR-193a-5p was significantly downregulated, whereas CXCR4 was significantly upregulated in tumor tissues obtained from patients with CRC compared with the adjacent non-tumor healthy controls. In addition, the upregulation of miR-193-5p reduced the expression levels of CXCR4, particularly in combination with 5-FU and OX. Besides, using rescue experiments, the present study showed that miR-193a-5p replacement was able to suppress CXCR4-induced CRC cell proliferation by directly targeting CXCR4. Furthermore, there was a significant association between miR-193a-5p and CXCR4 with certain clinicopathological characteristics, particularly with metastasis-related features. These results suggest that miR-193a-5p serves a tumor-suppressive function in CRC and can directly target CXCR4 and decrease its mRNA and protein expression levels. Additionally, miR-193a-5p in combination with 5-FU and Ox potentiated reducing CXR4 expression, which may reveal its contribution to tumor chemoresistance. In conclusion, miR-193-5p may be applicable as a prognostic and diagnostic marker, and also serve as a therapeutic factor by reducing CXCR4 in combination with chemotherapeutic drugs.

Harmful effects of high amounts of glucose on the immune system: An updated review.

Release and storage of energy can be regulated by the metabolic parameter dependent on the central nervous system. Macrophages are one of the most professional antigen-presenting cells that are formed by the accumulation of dead or damaged cells or in response to the infection, which has the main function of phagocytosis, secretion of cytokines, and presenting antigen to T cells. A proper immune response is needed for the production of effector cytokines along with comprehensive and rapid cell proliferation and growth. Activation of the immune system and immune cells is needed to increase glucose metabolism. When the immune system responds to pathogens, chemokines inform immune cells such as macrophages and T cells to travel to the infected area. Although glucose is vital for the proper function of immune cells and their proliferation, a high amount of glucose may lead to impaired function of the immune system and pathological conditions. However, a suitable amount of glucose is indispensable for the immune system, but its elevated amount leads to excessive proinflammatory cytokines production. In this study, we focused on the master regulatory role of glucose on the immune system.

Heat Shock Proteins Regulating Toll-like Receptors and the Immune System could be a Novel Therapeutic Target for Melanoma.

Melanoma is a serious type of skin cancer, which develops in melanocyte cells. Although it is less common than some other skin cancers, it can be far more dangerous if not treated at an early stage because of its ability to spread rapidly to other organs. Heat shock proteins (HSP) are intracellular molecular chaperones of naive proteins, which are induced in response to stressful conditions. HSP is released into the extracellular milieu and binds to Toll-like receptors (TLRs) to regulate immune responses, such as cytokine and chemokine release. HSPs can release and bind to tumor-specific antigens, with cross-presentation of major histocompatibility complex (MHC) class I antigens. TLRs are innate immune system receptors, involved in the melanoma growth pathway through HSP activation. Melanocytes express TLR4 and TLR9 to modulate immune responses. Many TLR ligands are considered as proper adjuvant candidates, as they can activate dendritic cells. Targeting some TLRs, such as TLR7 and TLR9, is an available option for treating melanoma. In this review, we aimed to determine the relationship between TLRs and HSP groups in melanoma.

E2 ubiquitin-conjugating enzymes in cancer: Implications for immunotherapeutic interventions.

Despite the medical advances of the 21st century, the incidence of cancer continues to increase and the search for a universal cure remains a major health challenge. Our lack of understanding the complex pathophysiology of the tumor microenvironment has hindered the development and efficiency of anti-cancer therapeutic strategies. The tumor microenvironment, composed of multiple cellular and non-cellular components, enables tumor-promoting processes such as proliferation, angiogenesis, migration and invasion, metastasis, and drug resistance. The ubiquitin-mediated degradation system is involved in several physiologic processes including cell cycling, signal transduction, receptor downregulation, endocytosis and transcriptional regulation. Ubiquitination includes attachment of ubiquitin to target proteins via E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. Several studies have shown that E2 enzymes are dysregulated in variety of cancers. Multiple investigations have demonstrated the involvement of E2s in various tumor-promoting processes including DNA repair, cell cycle progression, apoptosis and oncogenic signaling. E2 enzymes consist of 40 members that facilitate ubiquitin-substrate conjugation thereby modulating the stability and interaction of various proteins. As such, E2s are potential biomarkers as diagnostic, prognostic and therapeutic tools. In this review, we discuss the role of E2s in modulating various types of cancer.

The role of DEAD-box RNA helicase p68 (DDX5) in the development and treatment of breast cancer.

RNA helicase p68 or DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 (DDX5) is a unique member of the highly conserved protein family, which is involved in a broad spectrum of biological processes, including transcription, translation, precursor messenger RNA processing or alternative splicing, and microRNA (miRNA) processing. It has been shown that p68 is necessary for cell growth and participates in the early development and maturation of some organs. Interestingly, p68 is a transcriptional coactivator of numerous oncogenic transcription factors, including nuclear factor-κß (NF-κß), estrogen receptor α (ERα), ß-catenin, androgen receptor, Notch transcriptional activation complex, p53 and signal transducer, and activator of transcription 3 (STAT3). Recent studies on the role of p68 (DDX5) in multiple dysregulated cellular processes in various cancers and its abnormal expression indicate the importance of this factor in tumor development. Discussion of the precise role of p68 in cancer is complex and depends on the cellular microenvironment and interacting factors. In terms of the deregulated expression of p68 in breast cancer and the high prevalence of this cancer among women, it can be informative to review the precise function of this factor in the breast cancer. Therefore, an attempt will be made in this review to clarify the tumorigenic function of p68 in association with its targeting potential for the treatment of breast cancer.

Transcranial near-infrared photobiomodulation attenuates memory impairment and hippocampal oxidative stress in sleep-deprived mice.

Sleep deprivation (SD) causes oxidative stress in the hippocampus and subsequent memory impairment. In this study, the effect of near-infrared (NIR) photobiomodulation (PBM) on learning and memory impairment induced by acute SD was investigated. The mice were subjected to an acute SD protocol for 72 h. Simultaneously, NIR PBM using a laser at 810 nm was delivered (once a day for 3 days) transcranially to the head to affect the entire brain of mice. The Barnes maze and the What-Where-Which task were used to assess spatial and episodic-like memories. The hippocampal levels of antioxidant enzymes and oxidative stress biomarkers were evaluated. The results showed that NIR PBM prevented cognitive impairment induced by SD. Moreover, NIR PBM therapy enhanced the antioxidant status and increased mitochondrial activity in the hippocampus of SD mice. Our findings revealed that hippocampus-related mitochondrial damage and extensive oxidative stress contribute to the occurrence of memory impairment. In contrast, NIR PBM reduced hippocampal oxidative damage, supporting the ability of 810 nm laser light to improve the antioxidant defense system and maintain mitochondrial survival. This confirms that non-invasive transcranial NIR PBM therapy ameliorates hippocampal dysfunction, which is reflected in enhanced memory function.

The effects of gene therapy with granulocyte-macrophage colony-stimulating factor in the regression of tumor masses in fibrosarcoma mouse model.

INTRODUCTION: Cytokine gene therapy is one of the cancer treatment strategies. Recently, granulocyte-monocyte colony-stimulating factor (GM-CSF), as an important cytokine in activating dendritic cells and boosting the anti-tumor immune responses, has been utilized as an immunotherapeutic agent in cancer gene therapy. The purpose of the present investigation was to study the GM-CSF gene therapy effects in regression of tumor masses in fibrosarcoma mouse model. MATERIALS AND METHODS: To investigate the therapeutic efficacy of GM-CSF, WEHI-164 tumor cells were transfected with murine GM-CSF plasmid. For cytokine production by transfected cells, enzyme-linked immunosorbent assay test was used. Fibrosarcoma mouse model established with transfected cells which were injected subcutaneously into Balb/c mice. Tumor sizes were measured by caliper. Mice were sacrificed and the tumors were extracted. The expression of GM-CSF was studied by real-time polymerase chain reaction (PCR) and immunoblotting. The expression of Ki-67 (a tumor proliferative marker) in tumor masses was studied by immunohistochemical staining. RESULTS: The group treated with GM-CSF indicated a decrease in tumor mass volume (P = 0.001). The results of western blotting and real-time PCR showed that GM-CSF expression increased in the group treated with GM-CSF (with a relative expression of 1.36). Immunohistochemical staining showed that Ki-67 expression has reduced in the group treated with GM-CSF. CONCLUSION: Monotherapy with GM-CSF has therapeutic effects on the regression of tumor masses in the fibrosarcoma mouse model.

Up-regulation of TLR2 and TLR4 in high mobility group Box1-stimulated macrophages in pulpitis patients.

OBJECTIVES: High Mobility Group Box1 (HMGB1) is a nonhistone, DNA-binding protein that serves a crucial role in regulating gene transcription and is involved in a variety of proinflammatory, extracellular activities. The aim of this study was to explore whether HMGB1 stimulation can up-regulate the expression of Toll-like Receptor 2 (TLR2) and Toll-like Receptor 4 (TLR4) on macrophages from pulpitis and to clarify the subsequent events involving Th17 cells and Th17 cell-associated cytokine changes. MATERIALS AND METHODS: Having prepared dental pulp tissues of pulpitis and healthy controls, macrophage were isolated and cultured. Macrophages were thereafter stimulated by HMGB1 time course. RT-QPCR, flowcytometer, immunofluorescence, Western blotting, and ELISA techniques were used in the present research. RESULTS: Our results showed that the expression of TLR2 and TLR4 on macrophages stimulated with HMGB1 increased in pulpitis compared with controls (macrophages without HMGB1 stimulation) with a statistical significance (P<0.001). In addition, the levels of IL-17, IL-23, and IL-6 in supernatants from cultured macrophages stimulated with HMGB1 from pulpitis increased, and NF-kB, the downstream target of TLR2 and TLR4, also showed a marked elevation after macrophages' stimulation by HMGB1. CONCLUSION: The evidence from the present study suggests that the enhanced TLR2 and TLR4 pathways and Th17 cell polarization may be due to HMGB1 stimulation in pulpitis.

The interplay of microRNAs and post-ischemic glutamate excitotoxicity: an emergent research field in stroke medicine.

Stroke is the second leading cause of death and the most common cause of adult disabilities among elderlies. It involves a complex series of mechanisms among which, excitotoxicity is of great importance. Also, miRNAs appear to play role in post-stroke excitotoxicity, and changes in their transcriptome occur right after cerebral ischemia. Recent data indicate that specific miRNAs such as miRNA-223, miRNA-181, miRNA-125a, miRNA-125b, miRNA-1000, miRNA-132 and miRNA-124a regulate glutamate neurotransmission and excitotoxicity during stroke. However, limitations such as poor in vivo stability, side effects and inappropriate biodistribution in miRNA-based therapies still exist and should be overcome before clinical application. Thence, investigation of the effect of application of these miRNAs after the onset of ischemia is a pivotal step for manipulating these miRNAs in clinical use. Given this, present review concentrates on miRNAs roles in post-ischemic stroke excitotoxicity.

A method of experimental rheumatoid arthritis induction using collagen type II isolated from chicken sternal cartilage.

At present, collagen­induced arthritis (CIA) is the best known and most extensively used model for the immunological and pathological characteristics of human rheumatoid arthritis (RA). This model is useful not only in aiding our understanding of the pathogenesis of this disease, but also in the development of new therapies. Bovine, porcine and human collagen has been used to induce CIA; however, response has been identified to vary between strains and injection conditions, and false positive results and reduced potency are common as a result of minor contaminants or deglycosylated protein. Therefore, in the present study, type II collagen (CII) was isolated and purified from chicken sternal cartilage and was found to successfully induce the RA model. Furthermore, T helper 17 (Th17) cells were observed to infiltrate the joint on day 45 following induction by CII. In vitro, expression of toll­like receptor 2 (TLR2) increased in peritoneal macrophages stimulated by CII. In addition, blockage of TLR2 was identified to markedly decrease levels of TGF­ß and IL­6 in the cell culture supernatant. The results indicate that CII isolated from chicken sternal cartilage may be recognized by TLR2 on macrophages, leading to TGF­ß and IL­6 production and subsequent activation of Th17 cells which mediates CIA development.

Over-expression of Hlx homeobox gene in DC2.4 dendritic cell enhances its maturation and antigen presentation.

Hlx as a Th1-specific transcription factor, it appears to drive maturation of Th1 and IFN-γ secretion in cooperation with T-bet. In this study, we established a stable Hlx-over-expressed dendritic cell line (DC2.4/Hlx), and investigated the possible effect of Hlx gene on maturation of dendritic cell-line (DC2.4). Results shown that over-expressed Hlx in DC2.4 up-regulated the transcription and expression of IFN-γ, increased the expression of maturation makers including CD40, CD80, CD86, MHC-I and MHC-II. Functional assay for DC2.4/Hlx showed that over-expressed Hlx increased the expression level of interleukin-12 in the supernatant and decreased DC endocytosis when cells were incubated in vitro. Furthermore, using a syngeneic T cell activation model, we found that DC2.4/Hlx could obviously present ovalbumin (OVA) antigen to T cell in OVA pre-immunized mice.

Toll-like receptors are potential therapeutic targets in rheumatoid arthritis.

Toll-like receptors (TLRs) are found on the membranes of pattern recognition receptors and not only play important roles in activating immune responses but are also involved in the pathogenesis of inflammatory disease, injury and cancer. Furthermore, TLRs are also able to recognize endogenous alarmins released by damaged tissue and necrosis and/or apoptotic cells and are present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands plays an important role in initiating and driving inflammatory diseases. Increasing data suggest a role for TLR signaling in rheumatoid arthritis, which is an autoimmune disease. Although their involvement is not comprehensively understood, the TLRs signaling transducers may provide potential therapeutic targets.