Toll-Like Receptors as Therapeutic Targets in Central Nervous System Tumors.

In recent years, progress has been made in understanding the pathological, genetic, and molecular heterogeneity of central nervous system (CNS) tumors. However, improvements in risk classification, prognosis, and treatment have not been sufficient. Currently, great importance has been placed to the tumor microenvironment and the immune system, which are very important components that influence the establishment and development of tumors. Toll-like receptors (TLRs) are innate immunite system sensors of a wide variety of molecules, such as those associated with microorganisms and danger signals. TLRs are expressed on many cells, including immune cells and nonimmune cells such as neurons and cancer cells. In the tumor microenvironment, activation of TLRs plays dual antitumoral (dendritic cells, cytotoxic T cells, and natural killer cells activation) and protumoral effects (tumor cell proliferation, survival, and resistance to chemotherapy) and constitutes an area of opportunities and challenges in the development of new therapeutic strategies. Several clinical trials have been carried out, and others are currently in process; however, the results obtained to date have been contradictory and have not led to a definitive position about the use of TLR agonists in adjuvant therapy during the treatment of central nervous system (CNS) tumors. In this review, we focus on recent advances in TLR agonists as immunotherapies for treatment of CNS tumors.

Strong inflammatory response and Th1-polarization profile in children with acute lymphoblastic leukemia without apparent infection.

Children with acute lymphoblastic leukemia (ALL) often present fever. Febrile states are usually associated with infectious processes that generate an inflammatory response involving various molecules, including cytokines. However, an inflammatory response may also occur in the absence of infection. We hypothesized that the levels of inflammatory cytokines are increased in children with ALL without apparent infection. The serum levels of 13 cytokines in 99 patients with ALL and 48 non-oncological patients without apparent infection were measured using multiplex analyte profiling technology (Luminex®). The concentration of circulating pro-inflammatory cytokines associated with fever was similar between patients with ALL and fever at diagnosis and those without fever. The levels of tumor necrosis factor α, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and IL-10 were higher in patients with ALL vs. the control group (P<0.05). Moreover, the levels of the T helper 1 (interferon­Î³ and IL-12) cytokines were higher in patients with ALL vs. the control group. Transforming growth factor ß was lower in patients with ALL vs. the control group (P<0.05). The levels of IL-1ß, IL-2, IL-4, IL-13, and IL-17 were similar in the two groups. Our results indicate that the circulating levels of seven of the important studied cytokines are elevated in patients with newly diagnosed ALL without apparent infection, reflecting a strong and deregulated inflammatory state in this disease, with a Th1-polarization profile.

Relevance of single-nucleotide polymorphisms in human TLR genes to infectious and inflammatory diseases and cancer.

Innate and adaptive immune responses in humans have evolved as protective mechanisms against infectious microorganisms. Toll-like receptors (TLRs) have an important role in the recognition of invading microorganisms. TLRs are the first receptors to detect potential pathogens and to initiate the immune response, and they form the crucial link between the innate and adaptive immune responses. TLRs also have an important role in the pathophysiology of infectious and inflammatory diseases. Increasing data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single-nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to infectious or inflammatory disease that might contribute to the pathogenesis of complex diseases such as cancer. The associations between diseases and SNPs are in the early stage of discovery. Important clinical insights are emerging, and these polymorphisms provide new understanding of common diseases. This review summarizes and discusses the studies that shed light on the relevance of these polymorphisms in human infectious and inflammatory diseases and cancer.

Leishmania mexicana lipophosphoglycan activates ERK and p38 MAP kinase and induces production of proinflammatory cytokines in human macrophages through TLR2 and TLR4.

Protozoan parasites of genus Leishmania are the causative agents of leishmaniasis. Leishmania promastigotes primarily infect macrophages in the host, where they transform into amastigotes and multiply. Lipophosphoglycan (LPG), the most abundant surface molecule of the parasite, is a virulence determinant that regulates the host immune response. Promastigotes are able to modulate this effect through LPG, creating a favourable environment for parasite survival, although the mechanisms underlying this modulation remain unknown. We analysed the participation of TLR2 and TLR4 in the production of cytokines and explored the possible phosphorylation of ERK and/or p38 MAP kinase signalling cascades in human macrophages stimulated with Leishmania mexicana LPG. The results show that LPG induced the production of TNF-α, IL-1ß, IL-12p40, IL-12p70 and IL-10 and led to phosphorylation of ERK and p38 MAP kinase. Specific inhibitors of ERK or p38 MAP kinases and mAbs against TLR2 and TLR4 reduced cytokine production and phosphorylation of both kinases. Our results suggest that L. mexicana LPG binds TLR2 and TLR4 receptors in human macrophages, leading to ERK and MAP kinase phosphorylation and production of pro-inflammatory cytokines.

Low frequency of Toll-like receptors 2 and 4 gene polymorphisms in Mexican patients and their association with type 2 diabetes.

Type 2 diabetes (T2D) is characterized by a chronic low-grade inflammatory state. SNP in Toll-like receptor (TLR) genes has been associated with impaired inflammatory response. We genotyped the TLR4/D299G, TLR4/T399I and TLR2/R753Q polymorphisms. Low frequency was found with no association with T2D, nevertheless the TLR2 SNP was associated with lower levels in HDL-cholesterol values.

Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes.

BACKGROUND: Amino acids have been shown to stimulate insulin secretion and decrease glycated hemoglobin (A1C) in patients with Type 2 diabetes. In vitro, glycine reduces tumor necrosis factor (TNF)-alpha secretion and increases interleukin-10 secretion in human monocytes stimulated with lipopolysaccharide. The aim of this study was to determine whether glycine modifies the proinflammatory profiles of patients with Type 2 diabetes. MATERIALS/SUBJECTS AND METHODS: Seventy-four patients, with Type 2 diabetes were enrolled in the study. The mean age was 58.5 yr, average age of diagnosis was 5 yr, the mean body mass index was 28.5 kg/m2, the mean fasting glucose level was 175.5 mg/dl and the mean A1C level was 8%. They were allocated to one of two treatments, 5 g/d glycine or 5 g/d placebo, po tid, for 3 months. RESULTS: A1C levels of patients given glycine were significantly lower after 3 months of treatment than those of the placebo group. A significant reduction in TNF-receptor I levels was observed in patients given glycine compared with placebo. There was a decrease of 38% in the interferon (IFN)-gamma level of the group treated with placebo, whereas that of the group treated with glycine increased up to 43%. These data showed that patients treated with glycine had a significant decrease in A1C and in proinflammatory cytokines and also an important increase of IFN-gamma. CONCLUSION: Treatment with glycine is likely to have a beneficial effect on innate and adaptive immune responses and may help prevent tissue damage caused by chronic inflammation in patients with Type 2 diabetes.

The innate immune response to Entamoeba histolytica lipopeptidophosphoglycan is mediated by toll-like receptors 2 and 4.

Entamoeba histolytica is a human pathogen that may invade the intestinal mucosa, causing amoebic colitis or hepatic abscesses when the trophozoites travel through the portal circulation to the liver. Lipopeptidophosphoglycan (LPPG) is a molecular pattern of E. histolytica recognized by the human immune system. Here we report that LPPG is exposed on the cell surface of E. histolytica trophozoites, and is recognized by the host through toll-like receptor (TLR) 2 and TLR4. Correspondingly, human embryonic kidney (HEK)-293 cells were rendered LPPG responsive through overexpression of TLR2 or TLR4/MD2. Moreover, co-expression of CD14 enhanced LPPG signal transmission through TLR2 and TLR4. The interaction of LPPG with TLR2 and TLR4 resulted in activation of NF-kappaB and release of interleukin (IL)-10, IL-12p40, tumour necrosis factor (TNF)-alpha, and IL-8 from human monocytes. Consistent with these findings, responsiveness of mouse macrophages lacking TLR2 expression (TLR2-/-) or functional TLR4 (TLR4d/d) to E. histolytica LPPG challenge was impaired while double deficient macrophages were unresponsive. In contrast to wild-type control and TLR2-/- animals succumbing to lethal shock syndrome, TLR4d/d mice were resistant to systemic LPPG challenge-induced pathology.