Galectins, β-galactoside-binding animal lectins, are differentially expressed by various immune cells as well as a wide range of other cell types. Extracellularly, galectins are able to exhibit bivalent or multivalent interactions with cell-surface glycans on various immune cells and exert various effects. These include cytokine and mediator production, cell adhesion, apoptosis, and chemoattraction. In addition, they can form lattices with cell-surface glycoprotein receptors, resulting in modulation of receptor functions, including clustering and endocytosis. Intracellularly, galectins can participate in signaling pathways and modulate biologic responses. These include apoptosis, cell differentiation, and cell migration. Thus, a large body of literature indicates that galectins play important roles in the immune and inflammatory responses through regulating the homeostasis and functions of immune cells. The use of mice deficient in individual galectins has provided additional evidence for the contributions of these proteins to these responses. Current research indicates that galectins play important roles in the development of acute inflammation as well as chronic inflammation associated with allergies, autoimmune diseases, atherosclerosis, infectious processes, and cancer. Thus, recombinant proteins or specific galectin inhibitors may be used as therapeutic agents for inflammatory diseases.

Galectins: regulators of acute and chronic inflammation

Various TLR agonists are currently under investigation in clinical trials for their ability to orchestrate antitumor immunity. The antitumor responses are largely attributed to their aptitude to stimulate APCs such as DCs which in turn, activate tumor-specific T cell responses. However, there is a potential for TLR signaling to occur on cells other than professional APCs that could negate antitumor responses or even worse, promote tumor growth. The impetus for this review is twofold. First, there is accumulating data demonstrating that the engagement of TLRs on different T cell subsets and different cancer types could promote tumor growth or conversely, contribute to antitumor responses. Second, the efficacy of TLR agonists as monotherapies to treat cancer patients has been limited. In this review, we discuss how TLR signaling within different T cell subsets and cancer cells can potentially impact the generation of antitumor responses. Based on evidence from preclinical models and clinical trials, we draw attention to several criteria that we believe must be considered when selecting TLR agonists for developing effective immunotherapeutic strategies against cancer.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.1012501

TLR agonists: our best frenemy in cancer immunotherapy

In the past decade, increasing efforts have been devoted to the study of galectins, a family of evolutionarily conserved glycan-binding proteins with multifunctional properties. Galectins function, either intracellularly or extracellularly, as key biological mediators capable of monitoring changes occurring on the cell surface during fundamental biological processes such as cellular communication, inflammation, development, and differentiation. Their highly conserved structures, exquisite carbohydrate specificity, and ability to modulate a broad spectrum of biological processes have captivated a wide range of scientists from a wide spectrum of disciplines, including biochemistry, biophysics, cell biology, and physiology. However, in spite of enormous efforts to dissect the functions and properties of these glycan-binding proteins, limited information about how structural and biochemical aspects of these proteins can influence biological functions is available. In this review, we aim to integrate structura...

When Galectins Recognize Glycans: From Biochemistry to Physiology and Back Again

Induction of antiviral innate immune responses depends on a family of innate immune receptors, the Toll-like receptors (TLR). TLR mediate the antiviral immune responses by recognizing virus infection, activating signaling pathways and inducing the production of antiviral cytokines and chemokines. ssRNA and dsRNA viruses can be recognized by TLR7/8 and TLR3, respectively. TLR receptors are also involved in the recognition of viruses containing genomes rich in CpG DNA motifs as well as envelope glycoproteins. Cytoplasmic recognition of dsRNA by RNA helicases such as RIG-I and MDA5 provides another means of recognizing viral nucleic acid. In order to counteract the innate host immune system viruses evolved mechanisms that block recognition and signaling through pattern recognition receptors, such as TLRs and RNA helicases. Recently, TLR agonists represent a promising approach for the treatment of infectious diseases. This review will focus on the current knowledge of TLR-mediated immune responses to several viral infections.

/pdf/toll-like-receptors-and-viruses-induction-of-innate-5cc67v8ohm.pdf

Toll-like receptors and viruses: induction of innate antiviral immune responses.

Identification of Interferon-Stimulated Genes with Antiretroviral Activity

Whether galectin-9 plays a role in inflammatory responses remains elusive. The present study was designed to determine the role of intracellular galectin-9 in activation of inflammatory cytokine genes in human monocytes. Galectin-9 expression vector pBKCMV3-G9 was transiently co-transfected into THP-1 monocytic cells along with luciferase reporters carrying gene promoters of IL-1alpha (IL1A), IL-1beta (IL1B) and IFNgamma. Transient transfection studies showed that galectin-9 over-expression activated all three gene promoters, suggesting that intracellular galectin-9 induces inflammatory cytokine genes in monocytes. Galectin-9 over-expression also activated NF-IL6 (C/EBP beta) and AP-1, but not NF-kappaB. In contrast, extracellular galectin-9 is not involved in regulation of inflammatory cytokines. Immunoprecipitation/Western blotting, using anti-galectin-9 Ab and anti-NF-IL6 Ab, showed physical association of intracellular galectin-9 with NF-IL6. RT-PCR confirmed that galectin-9 over-expression increased IL-1alpha and IL-1beta mRNA levels in THP-1 cells. The interaction of galectin-9 with NF-IL6 was enhanced following LPS treatment in THP-1 cells. Intracellular galectin-9 synergized with LPS to activate NF-IL6. Nuclear translocation of galectin-9 was also observed in THP-1 cells treated with LPS. Our results indicate that galectin-9 is a LPS-responsive factor, and further demonstrate that intracellular galectin-9 transactivates inflammatory cytokine genes in monocytes through direct physical interaction with NF-IL6.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2443.2009.01287.x

Intracellular galectin-9 activates inflammatory cytokines in monocytes

Activation of c-jun N-terminal kinase (JNK) through c-kit-mediated phosphatidylinositol 3 (PI3) and Src kinase pathways plays an important role in cell proliferation and survival in mast cells. Gain-of-function mutations in c-kit are found in several human neoplasms. Constitutive activation of c-kit has been observed in human mastocytosis and gastrointestinal stromal tumor. In the present study, we demonstrate that an anthrapyrazole SP600125, a reversible ATP-competitive inhibitor of JNK inhibits proliferation of human HMC-1 mast cells expressing constitutively activated c-kit catalytic domain mutations. HMC-1 showed constitutive activation of JNK/c-Jun, and the inhibitory effect of SP600125 on cell proliferation was associated with cell cycle arrest at the G 1 phase and apoptosis accompanied by cleavage of caspase-3 and PARP. Caspase-3 inhibitor Z-DEVD-FMK almost completely inhibited SP600125-induced apoptosis of HMC-1 cells. In contrast, caspase-9 inhibitor Z-LEHD-FMK failed to block SP600125-induced apoptosis. Following SP600125 treatment, down-regulation of cyclin D3 protein expression, but not p53 was also observed. Thus, JNK/c-Jun is essential for proliferation and survival of HMC-1 cells. The results obtained from the present study suggest the possibility that JNK/c-Jun may be a therapeutic target in diseases associated with mutations in the catalytic domain of c-kit.

Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125.

https://www.exphem.org/article/S0301-472X(07)00496-1/pdf

Constitutive association of MyD88 to IRAK in HTLV-I–transformed T cells

The efficacy of Micafungin as an empiric therapy for febrile neutropenic patients refractory to antibacterial agents

A 71-year-old woman was admitted in December 2002 because of lymphadenopathy, hepatosplenomegaly and pleural effusion. She had severe anemia with hemoglobin 5.9 g/dl and a reticulocyte count of 1% per hundred. Direct/indirect Coombs tests and anti-double stranded DNA antibody were positive, her serum CH50 level was reduced and an increase in serum LDH isoenzyme 3 was observed. Bone marrow aspiration showed an almost total absence of erythroblasts and no pathological cell proliferation. The diagnosis of angioimmunoblastic T-cell lymphoma (AILT) was made based on the lymph node histological findings. Proliferation of arborizing small vessels with hyperplastic endothelium and infiltration of atypical T-lymphocytes were observed. After combination chemotherapy (THP-COP), remission was achieved in both the pure red cell aplasia (PRCA) and AILT. Remission was also accompanied by normalization of the Coombs tests, suggesting that autoimmune mechanisms in AILT may contribute to the development of PRCA.

Ai Matsuura

Papers

Intracellular galectin-9 activates inflammatory cytokines in monocytes

Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125.

Constitutive association of MyD88 to IRAK in HTLV-I–transformed T cells

The efficacy of Micafungin as an empiric therapy for febrile neutropenic patients refractory to antibacterial agents

[Angioimmunoblastic T-cell lymphoma accompanied by pure red cell aplasia].