Rosclerosis in subjects without metabolic syndrome, even after adjusting for other cardiovascular risk factors. Progranulin, also known as proepithelin or acrogranin, is a widely-expressed, 593 amino acid secreted glycoprotein [18]. Reported biological activities of EPZ015666 web progranulin include growth factor-like activities, modulation of immune responses, and neuronal effects [19]. Recently, Tang et al. found that progranulin is a ligand of TNFR and the anti-inflammatory effects of progranulin are mainly mediated by inhibition of TNF-a-activatedHOMA-IR eGFR IL-6 hsCRP AdiponectinCTRP-3, C1q/TNF-related protein-3; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein;HOMA-IR, homeostasis model assessment of insulin resistance; eGFR, estimated glomerular filtration rate;IL-6, interleukin-6; hsCRP, highsensitivity C-reactive protein;IMT, intima-media thickness. doi:10.1371/journal.pone.0055744.tintracellular signaling; Treatment of bone marrow-derived macrophages with recombinant progranulin inhibited TNF-a-induced phosphorylation of p38, c-jun N-terminal kinase (JNK), and the mitogen-activated protein kinase (MAPK) family, and impaired NF-kB nuclear translocation [5]. They have shown that progranulin prevents mice from inflammatory arthritis by blockingFigure 1. Serum C1q/TNF-related Protein-3 (CTRP3) (A) and Progranulin Levels (B) According to Number of Metabolic Syndrome Components. doi:10.1371/journal.pone.0055744.gProgranulin and CTRP3 in Metabolic SyndromeTable 3. Multiple Stepwise Regression Analyses for Determinant Factors Associated With Carotid Intima-Media Thickness in Subjects With or Without Metabolic Syndrome.B Subjects without metabolic syndrome (R = 0.365) (Constant) Age Sex Body mass index HDL-cholesterol Progranulin 0.014 0.008 20.045 0.010 20.002 0.SEP0.147 0.001 0.026 0.004 0.001 0.0.927 0.000 0.085 0.019 0.059 0.Subjects with metabolic syndrome (R2 = 0.433) (Constant) Age Diastolic blood pressure LDL-cholesterol 20.268 0.011 0.004 0.001 0.268 0.002 0.002 0.001 0.324 0.000 0.122 0.Independent variables for mean IMT: age, sex, body mass index, systolic blood pressure, diastolic blood pressure, HDL-cholesterol, triglycerides, LDLcholesterol, fasting glucose, hsCRP, adiponectin and progranulin levels. SE, standard error; R2, coefficient of determination. doi:10.1371/journal.pone.0055744.tinteraction with TNF-a [5]. However, not all the actions of progranulin on inflammatory cells are inhibitory, and the interactions between progranulin and inflammation were reported to be more complicated in some previous reports. During the inflammatory process, progranulin is digested into smaller peptides, called granulins, that are pro-inflammatory and neutralize the anti-inflammatory effect of intact progranulin [6]. Moreover, Okura et al. reported that progranulin increased the expression of TNF-a and IL-1b in human monocyte-derived macrophages [20]. In a cutaneous wound, progranulin promoted the accumulation of neutrophils and macrophages, suggesting the chemotactic activity of progranulin for inflammatory cells [21]. Furthermore, we previously reported that elevated progranulin serum concentrations were positively associated with omental adipose Desoxyepothilone B tissue macrophage infiltration and increased in subjects with type 2 diabetes, suggesting progranulin as a chemoattractant molecule [8]. These results support the hypothesis that progranulin may play dual roles in the inflammator.Rosclerosis in subjects without metabolic syndrome, even after adjusting for other cardiovascular risk factors. Progranulin, also known as proepithelin or acrogranin, is a widely-expressed, 593 amino acid secreted glycoprotein [18]. Reported biological activities of progranulin include growth factor-like activities, modulation of immune responses, and neuronal effects [19]. Recently, Tang et al. found that progranulin is a ligand of TNFR and the anti-inflammatory effects of progranulin are mainly mediated by inhibition of TNF-a-activatedHOMA-IR eGFR IL-6 hsCRP AdiponectinCTRP-3, C1q/TNF-related protein-3; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein;HOMA-IR, homeostasis model assessment of insulin resistance; eGFR, estimated glomerular filtration rate;IL-6, interleukin-6; hsCRP, highsensitivity C-reactive protein;IMT, intima-media thickness. doi:10.1371/journal.pone.0055744.tintracellular signaling; Treatment of bone marrow-derived macrophages with recombinant progranulin inhibited TNF-a-induced phosphorylation of p38, c-jun N-terminal kinase (JNK), and the mitogen-activated protein kinase (MAPK) family, and impaired NF-kB nuclear translocation [5]. They have shown that progranulin prevents mice from inflammatory arthritis by blockingFigure 1. Serum C1q/TNF-related Protein-3 (CTRP3) (A) and Progranulin Levels (B) According to Number of Metabolic Syndrome Components. doi:10.1371/journal.pone.0055744.gProgranulin and CTRP3 in Metabolic SyndromeTable 3. Multiple Stepwise Regression Analyses for Determinant Factors Associated With Carotid Intima-Media Thickness in Subjects With or Without Metabolic Syndrome.B Subjects without metabolic syndrome (R = 0.365) (Constant) Age Sex Body mass index HDL-cholesterol Progranulin 0.014 0.008 20.045 0.010 20.002 0.SEP0.147 0.001 0.026 0.004 0.001 0.0.927 0.000 0.085 0.019 0.059 0.Subjects with metabolic syndrome (R2 = 0.433) (Constant) Age Diastolic blood pressure LDL-cholesterol 20.268 0.011 0.004 0.001 0.268 0.002 0.002 0.001 0.324 0.000 0.122 0.Independent variables for mean IMT: age, sex, body mass index, systolic blood pressure, diastolic blood pressure, HDL-cholesterol, triglycerides, LDLcholesterol, fasting glucose, hsCRP, adiponectin and progranulin levels. SE, standard error; R2, coefficient of determination. doi:10.1371/journal.pone.0055744.tinteraction with TNF-a [5]. However, not all the actions of progranulin on inflammatory cells are inhibitory, and the interactions between progranulin and inflammation were reported to be more complicated in some previous reports. During the inflammatory process, progranulin is digested into smaller peptides, called granulins, that are pro-inflammatory and neutralize the anti-inflammatory effect of intact progranulin [6]. Moreover, Okura et al. reported that progranulin increased the expression of TNF-a and IL-1b in human monocyte-derived macrophages [20]. In a cutaneous wound, progranulin promoted the accumulation of neutrophils and macrophages, suggesting the chemotactic activity of progranulin for inflammatory cells [21]. Furthermore, we previously reported that elevated progranulin serum concentrations were positively associated with omental adipose tissue macrophage infiltration and increased in subjects with type 2 diabetes, suggesting progranulin as a chemoattractant molecule [8]. These results support the hypothesis that progranulin may play dual roles in the inflammator.
