The role of IL-33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate timedependent increase of endogenous IL-33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL-33 accelerated tumor growth and development of lung and liver metastases, which was associated with increased intratumoral accumulation of CD11b 1 Gr-1 1 TGF-b1 1 myeloid-derived suppressor cells (MDSCs) that expressed IL-13a1R, IL-13-producing Lin 2 Sca-1 1 ST2 1 innate lymphoid cells (ILCs) and CD4 1 Foxp3 1 ST2 1 IL-10 1 Tregs compared to untreated mice. Higher incidence of monocytic vs. granulocytic MDSCs and plasmocytoid vs. conventional dendritic cells (DCs) was present in mammary tumors of IL-33-treated mice. Intratumoral NKp46 1 NKG2D 1 and NKp46 1 FasL 1 cells were markedly reduced after IL-33 treatment, while phosphate-buffered saline-treated ST2-deficient mice had increased frequencies of these tumoricidal natural killer (NK) cells compared to untreated wild-type mice. IL-33 promoted intratumoral cell proliferation and neovascularization, which was attenuated in the absence of ST2. Tumor-bearing mice given IL-33 had increased percentages of splenic MDSCs, Lin 2 Sca-1 1 ILCs, IL-10-expressing CD11c 1 DCs and alternatively activated M2 macrophages and higher circulating levels of IL-10 and IL-13. A significantly reduced NK cell, but not CD8 1 T-cell cytotoxicity in IL-33-treated mice was observed and the mammary tumor progression was not affected when CD8 1 T cells were in vivo depleted. We show a previously unrecognized role for IL-33 in promoting breast cancer progression through increased intratumoral accumulation of immunosuppressive cells and by diminishing innate antitumor immunity. Therefore, IL-33 may be considered as an important mediator in the regulation of breast cancer progression.Interleukin-33 (IL-33), a member of the IL-1 family, is a multifunctional cytokine released upon necrotic cell death, which secretion can also be induced in live cells under biomechanical stress conditions. 1 IL-33 is primarily expressed in nonhematopoietic cells including fibroblasts, epithelial cells and endothelial cells, but is also present in cells of hematopoietic origin, particularly in macrophages and dendritic cells (DCs). 2,3 IL-33 regulates innate and acquired immunity 3-6 through binding to membrane-bound ST2 molecule (ST2L) of the IL-33R complex expressed on murine and human Th2 cells, mast cells, natural killer (NK) cells, myeloid cells and DCs. 3,7 IL-33 promotes Th2 immune response 2,3 and polarization of alternatively activated M2 macrophages. 8 Newly identified Type 2 innate lymphoid cells (ILC2) produce large amounts of IL-5 and IL-13 in response to IL-33 in the intestine, 9 adipose tissue 10 and lungs. 11 However, IL-33 could activate Th1, NK, NKT and CD8 1 T cells under certain pathophysiological conditions. IL-33 has a dual role in inflammatory disorders; it has protective effects in obesity, atherosclerosis and experiment...

Obesity-induced diabetes is associated with low-grade inflammation in adipose tissue and macrophage infiltration of islets. We show that ablation of galectin-3 (Gal-3), a galactoside-binding lectin, accelerates high-fat diet–induced obesity and diabetes. Obese LGALS3−/− mice have increased body weight, amount of total visceral adipose tissue (VAT), fasting blood glucose and insulin levels, homeostasis model assessment of insulin resistance, and markers of systemic inflammation compared with diet-matched wild-type (WT) animals. VAT of obese LGALS3−/− mice exhibited increased incidence of type 1 T and NKT lymphocytes and proinflammatory CD11c+CD11b+ macrophages and decreased CD4+CD25+FoxP3+ regulatory T cells and M2 macrophages. Pronounced mononuclear cell infiltrate, increased expression of NLRP3 inflammasome and interleukin-1β (IL-1β) in macrophages, and increased accumulation of advanced glycation end products (AGEs) and receptor for AGE (RAGE) expression were present in pancreatic islets of obese LGALS3−/− animals accompanied with elevated phosphorylated nuclear factor-κB (NF-κB) p65 and mature caspase-1 protein expression in pancreatic tissue and VAT. In vitro stimulation of LGALS3−/− peritoneal macrophages with lipopolysaccharide (LPS) and saturated fatty acid palmitate caused increased caspase-1–dependent IL-1β production and increased phosphorylation of NF-κB p65 compared with WT cells. Transfection of LGALS3−/− macrophages with NLRP3 small interfering RNA attenuated IL-1β production in response to palmitate and LPS plus palmitate. Obtained results suggest important protective roles for Gal-3 in obesity-induced inflammation and diabetes.

The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. To dissect the role of Gal-3 in fibrotic nonalcoholic steatohepatitis (NASH), Gal-3-deficient (LGALS3 -/-) and wild-type (LGALS3 +/+ ) C57Bl/6 mice were placed on an obesogenic high fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 wks. Compared to WT mice, HFD-fed LGALS3 -/-mice developed, in addition to increased visceral adiposity and diabetes, marked liver steatosis, which was accompanied with higher expression of hepatic PPAR-γ, Cd36, Abca-1 and FAS. However, as opposed to LGALS3 -/-mice, hepatocellular damage, inflammation and fibrosis were more extensive in WT mice which had an elevated number of mature myeloid dendritic cells, proinflammatory CD11b + Ly6C hi monocytes/macrophages in liver, peripheral blood and bone marrow, and increased hepatic CCL2, F4/80, CD11c, TLR4, CD14, NLRP3 inflammasome, IL-1β and NADPH-oxidase enzymes mRNA expression. Thus, obesitydriven greater steatosis was uncoupled with attenuated fibrotic NASH in Gal-3-deficient mice. HFD-fed WT mice had a higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b genotypes, albeit to a significantly lower extent in LGALS3 -/-mice, which was associated with less numerous hepatic IL-13-expressing CD11b + cells. The present study provides evidence of a novel role for Gal-3 in regulating IL-33-dependent liver fibrosis. adipose tissue and islets where dendritic cells (DCs) and macrophages play important roles (11). The data on the effect of Gal-3 ablation in liver steatosis/inflammation are controversial. Nomoto et al. (13) showed that Gal-3-deficient mice spontaneously developed steatosis at six months of age and that a lack of Gal-3 led to greater steatosis and liver injury in the model of CDAA diet-induced NASH (14). On the other hand, in a study by Iacobini et al. (15) Gal-3 null mice fed an atherogenic diet were resistant to the development of steatosis and NASH. In the liver, Gal-3 is highly expressed in Kupffer cells and its expression is increased during hepatocellular damage (16). The essential step in hepatic inflammation and fibrogenesis is CCL2-mediated monocyte recruitment (17,18). Resident and recruited liver macrophages may be polarized toward classically activated macrophages (M1), which promote survival of hepatic myofibroblasts by secreted TNF-α and IL-1β, and, alternatively, macrophages that express the Th2-type cytokines (M2), including IL-13, which directly stimulates collagen synthesis in myofibroblasts (19)(20)(21). Macrophage-derived Gal-3 has been shown to promote myofibroblast activation in liver fibrosis (22,23). The disruption of the Gal-3 gene was reported to block TGF-β mediated myofibroblast activation and procollagen expression and markedly attenuated CCl 4 -induced liver fibrosis in mice (22). Interleukin-33 (IL-33), a damage-associated molecular pattern (DAMP) molecule, could induce IL-13 production by macrophages to promote type 2 immunity (24). IL-33 has a profibrogenic role ...

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Renewing interest in immune aspects of schizophrenia and new findings about the brain-fat axis encourage us to discuss the possible role of interleukin-6 (IL-6) in schizophrenia. Previously, it was suggested that a primary alteration of the innate immune system may be relevant in schizophrenia. Functional dichotomy of IL-6 suggests that this chemical messenger may be responsible for regulating the balance between pro- and anti-inflammatory responses, with tissue-specific properties at the periphery and in the central nervous system. Specific phase of this chronic and deteriorating disorder must be considered, which can involve IL-6 in acute or possible chronic inflammation and/or autoimmunity. We give an overview of IL-6 role in the onset and progression of this disorder, also considering cognitive impairment and metabolic changes in patients with schizophrenia. Data suggest that decreased serum level of IL-6 following antipsychotic therapy could be predisposing factor for the development of obesity and obesity-related metabolic disorders in schizophrenia. As we reviewed, the IL-6 plays significant role in disease genesis and progression, so the use of specific inhibitors may not only be beneficial for exacerbation and alleviation of positive symptoms, but may attenuate cognitive impairment in patients with schizophrenia.