A critical role for IL-17, a cytokine produced by T helper 17 (Th17) cells, has been indicated in the pathogenesis of chronic inflammatory and autoimmune diseases. A positive effect of blockade of IL-17 secreted by autoreactive T cells has been shown in various inflammatory diseases. Several cytokines, whose production is affected by environmental factors, control Th17 differentiation and its maintenance in tissues during chronic inflammation. The roles of IL-17 in the pathogenesis of chronic neuroinflammatory conditions, multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), Alzheimer's disease, and ischemic brain injury are reviewed here. The role of environmental stimuli in Th17 differentiation is also summarized, highlighting the role of viral infection in the regulation of pathogenic T helper cells in EAE.

Gal-3 has the role in multiple inflammatory pathways. Multiple-hit etiology of primary biliary cholangitis (PBC) and evolving immune response at various stages of the disease includes involvement of Gal-3 in PBC pathogenesis. In this study we aimed to clarify the role of Gal-3 in Novosphingobium aromaticivorans ( N. aromaticivorans ) induced biliary disease. Autoimmune cholangitis was induced in mice by two intra-peritoneal injections of N. aromaticivorans within 2 weeks. The role of Gal-3 was evaluated by using Lgals3 −/− mice and mice treated with Gal-3 inhibitor. The histological and serological parameters of disease, phenotype of dendritic, NK, NKT, and T cells and inflammasome expression were evaluated. Marked attenuation of the disease in Lgals3 −/− and Gal-3 inhibitor, DAVANAT ® , treated mice is manifested by the absence of bile duct damage, granulomas and fibrosis. Liver infiltrates of N. aromaticivorans infected wild type mice had higher incidence of pro-inflammatory macrophages, dendritic cells, NK, NKT, and T cells. Lgals3 deletion and treatment with Gal-3 inhibitor reduced inflammatory mononuclear cell infiltrate, expression of NLRP3 inflammasome in the liver infiltrates and interleukin-1β (IL-1β) production in the livers of N. aromaticivorans infected mice. In vitro stimulation of wild type peritoneal macrophages with N. aromaticivorans caused increased NLRP3 expression, caspase-1 activity and IL-1β production compared with Lgals3 −/− cells. Our data highlight the importance of Gal-3 in promotion of inflammation in N. aromaticivorans induced PBC by enhancing the activation of NLRP3 inflammasome and production of IL-1β and indicate Gal-3 as possible therapeutical target in autoimmune cholangitis. Galectin-3 appears involved in inflammatory response to gut commensal leading to PBC.

Galectin-3 (Gal-3) is a carbohydrate binding lectin, with multiple roles in inflammatory diseases and autoimmunity including its antiapoptotic effect on epithelial cells. In particular, increased expression of Gal-3 in epithelial cells is protective from apoptosis. Based on the thesis that apoptosis of biliary epithelial cells (BECs) is critical to the pathogenesis of Primary Biliary Cholangitis (PBC), we have analyzed the role of Gal-3 in the murine model of autoimmune cholangitis. We took advantage of Gal-3 knockout mice and immunized them with a mimotope of the major mitochondrial autoantigen of PBC, 2-octynoic acid (2-OA) coupled to BSA (2OA-BSA) and evaluated the natural history of subsequent disease, compared to control wild-type mice, by measuring levels of antibodies to PDC-E2, immunohistology of liver, and expression of Gal-3. We report herein that deletion of Gal-3 significantly exacerbates autoimmune cholangitis in these mice. This is manifested by increased periportal infiltrations, bile duct damage, granulomas and fibrosis. Interestingly, the BECs of Gal-3 knockout mice had a higher response to apoptotic stimuli and there were more pro-inflammatory lymphocytes and dendritic cells (DCs) in the livers of Gal-3 knockout mice. In conclusion, Gal-3 plays a protective role in the pathways that lead to the inflammatory destruction of biliary epithelial cells.

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Ruthenium complexes have attracted considerable interest as potential antitumor agents. Therefore, antitumor activity and systemic toxicity of ruthenium(II) terpyridine complexes were evaluated in heterotopic mouse colon carcinoma. In the present study, cytotoxic effects of recently synthesized ruthenium(II) terpyridine complexes [Ru(Cl-tpy)(en)Cl][Cl] (en = ethylenediamine, tpy = terpyridine, Ru-1) and [Ru(Cl-tpy)(dach)Cl][Cl] (dach = 1,2-diaminocyclohexane, Ru-2) towards human and murine colon carcinoma cells were tested in vitro and in vivo and compared with oxaliplatin, the most commonly used chemotherapeutic agent against colorectal carcinoma. Ruthenium(II) complexes showed moderate cytotoxicity with IC50 values ranging between 19.1 to 167.3 μM against two human, HCT116 and SW480, and one mouse colon carcinoma cell line, CT26. Both ruthenium(II) terpyridine complexes exerted a moderate apoptotic effect in colon carcinoma cells, but induced significant necrotic death. Additionally, both complexes induced cell cycle disturbances, but these effects were specific for the cell line. Further, Ru-1 significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin. Renal damage in Ru-1 treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but Ru-1 induced higher liver damage than oxaliplatin, evaluated by the serum levels of alanine aminotransferase. Additionally, the interaction of these ruthenium(II) terpyridine complexes with the tripeptide glutathione (GSH) was investigated by proton nuclear magnetic resonance (1H NMR) spectroscopy. All reactions led to the formation of monofunctional thiolate adducts [Ru(Cl-tpy)(en)GS-S] (3) and [Ru(Cl-tpy)(dach)GS-S] (4). Our data highlight the significant cytotoxic activity of [Ru(Cl-tpy)(en)Cl][Cl] against human and mouse colon carcinoma cells, as well as in vivo antitumor activity in CT26 tumor-bearing mice similar to standard chemotherapeutic oxaliplatin, accompanied with lower nephrotoxicity in comparison with oxaliplatin.

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.

In contrast to C57BL/6 mice, BALB/c mice are relatively resistant to the induction of experimental autoimmune encephalomyelitis (EAE) after challenge with MOG35–55 peptide. Here, we provide the first evidence that infection with murine cytomegalovirus (MCMV) in adulthood abrogates this resistance. Infected BALB/c mice developed clinical and histological signs similar to those seen in susceptible C57BL/6 mice. In addition to CD4+ cells, large proportion of cells in the infiltrate of diseased BALB/c mice was CD8+, similar with findings in multiple sclerosis. CD8+ cells that responded to ex vivo restimulation with MOG35–55 were not specific for viral epitopes pp89 and m164. MCMV infection favors proinflammatory type of dendritic cells (CD86+CD40+CD11c+) in the peripheral lymph organs, M1 type of microglia in central nervous system, and increases development of Th1/Th17 encephalitogenic cells. This study indicates that MCMV may enhance autoimmune neuropathology and abrogate inherent resistance to EAE in mouse strain by enhancing proinflammatory phenotype of antigen-presenting cells, Th1/Th17, and CD8 response to MOG35–55.

Galectin-3 (Gal-3) has a role in multiple inflammatory pathways. Various, opposite roles of Gal-3 in liver diseases have been described but there are no data about the role of Gal-3 in development of hepatitis induced with cytomegalovirus infection. In this study we aimed to clarify the role of Gal-3 in murine cytomegalovirus (MCMV)-induced hepatitis by using Gal-3–deficient (Gal-3 KO) mice. Here we provide the evidence that Gal-3 has the protective role in MCMV-induced hepatitis. Enhanced hepatitis manifested by more inflammatory and necrotic foci and serum level of ALT, enhanced apoptosis and necroptosis of hepatocytes and enhanced viral replication were detected in MCMV-infected Gal-3 deficient mice. NK cells does not contribute to more severe liver damage in MCMV-infected Gal-3 KO mice. Enhanced expression of TNF-α in the hepatocytes of Gal-3 KO mice after MCMV infection, abrogated hepatocyte death, and attenuated inflammation in the livers of Gal-3 KO mice after TNF-α blockade suggest that TNF-α plays the role in enhanced disease in Gal-3 deficient animals. Treatment with recombinant Gal-3 reduces inflammation and especially necrosis of hepatocytes in the livers of MCMV-infected Gal-3 KO mice. Our data highlight the protective role of Gal-3 in MCMV-induced hepatitis by attenuation of TNF-α-mediated death of hepatocytes.