Hesperetin derivative-12 (HDND-12) regulates macrophage polarization by modulating JAK2/STAT3 signaling pathway
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摘要
Macrophages show significant heterogeneity in function and phenotype, which could shift into different populations of cells in response to exposure to various micro-environmental signals. These changes, also termed as macrophage polarization, of which play an important role in the pathogenesis of many diseases. Numerous studies have proved that Hesperidin(HDN), a traditional Chinese medicine, extracted from fruit peels of the genus citrus, play key roles in anti-inflammation, anti-tumor, anti-oxidant and so on. However, the role of HDN in macrophage polarization has never been reported. Additional, because of its poor water solubility and bioavailability. Our laboratory had synthesized many hesperidin derivatives. Among them, hesperidin derivatives-12(HDND-12) has better water solubility and bioavailability. So, we evaluated the role of HDND-12 in macrophage polarization in the present study. The results showed that the expression of Arginase-1(Arg-1), interleukin-10(IL-10), transforming growth factor β(TGF-β) were up-regulated by HDND-12, whereas the expression of inducible Nitric Oxide Synthase(iNOS) was down-regulated in LPS-and IFN-γ-treated(M1) RAW264.7 cells. Moreover, the expression of p-JAK2 and p-STAT3 were significantly decreased after stimulation with HDND-12 in M1-like macrophages. More importantly, when we taken AG490(inhibitor of JAK2/STAT3 signaling), the protein levels of iNOS were significantly reduced in AG490 stimulation group compare with control in LPS, IFN-γ and HDND-12 stimulation cells. Taken together, these findings indicated that HDND-12 could prevent polarization toward M1-like macrophages, at least in part, through modulating JAK2/STAT3 pathway.
Macrophages show significant heterogeneity in function and phenotype, which could shift into different populations of cells in response to exposure to various micro-environmental signals. These changes, also termed as macrophage polarization, of which play an important role in the pathogenesis of many diseases. Numerous studies have proved that Hesperidin(HDN), a traditional Chinese medicine, extracted from fruit peels of the genus citrus, play key roles in anti-inflammation, anti-tumor, anti-oxidant and so on. However, the role of HDN in macrophage polarization has never been reported. Additional, because of its poor water solubility and bioavailability. Our laboratory had synthesized many hesperidin derivatives. Among them, hesperidin derivatives-12(HDND-12) has better water solubility and bioavailability. So, we evaluated the role of HDND-12 in macrophage polarization in the present study. The results showed that the expression of Arginase-1(Arg-1), interleukin-10(IL-10), transforming growth factor β(TGF-β) were up-regulated by HDND-12, whereas the expression of inducible Nitric Oxide Synthase(iNOS) was down-regulated in LPS-and IFN-γ-treated(M1) RAW264.7 cells. Moreover, the expression of p-JAK2 and p-STAT3 were significantly decreased after stimulation with HDND-12 in M1-like macrophages. More importantly, when we taken AG490(inhibitor of JAK2/STAT3 signaling), the protein levels of iNOS were significantly reduced in AG490 stimulation group compare with control in LPS, IFN-γ and HDND-12 stimulation cells. Taken together, these findings indicated that HDND-12 could prevent polarization toward M1-like macrophages, at least in part, through modulating JAK2/STAT3 pathway.
Macrophages show significant heterogeneity in function and phenotype, which could shift into different populations of cells in response to exposure to various micro-environmental signals. These changes, also termed as macrophage polarization, of which play an important role in the pathogenesis of many diseases. Numerous studies have proved that Hesperidin(HDN), a traditional Chinese medicine, extracted from fruit peels of the genus citrus, play key roles in anti-inflammation, anti-tumor, anti-oxidant and so on. However, the role of HDN in macrophage polarization has never been reported. Additional, because of its poor water solubility and bioavailability. Our laboratory had synthesized many hesperidin derivatives. Among them, hesperidin derivatives-12(HDND-12) has better water solubility and bioavailability. So, we evaluated the role of HDND-12 in macrophage polarization in the present study. The results showed that the expression of Arginase-1(Arg-1), interleukin-10(IL-10), transforming growth factor β(TGF-β) were up-regulated by HDND-12, whereas the expression of inducible Nitric Oxide Synthase(iNOS) was down-regulated in LPS-and IFN-γ-treated(M1) RAW264.7 cells. Moreover, the expression of p-JAK2 and p-STAT3 were significantly decreased after stimulation with HDND-12 in M1-like macrophages. More importantly, when we taken AG490(inhibitor of JAK2/STAT3 signaling), the protein levels of iNOS were significantly reduced in AG490 stimulation group compare with control in LPS, IFN-γ and HDND-12 stimulation cells. Taken together, these findings indicated that HDND-12 could prevent polarization toward M1-like macrophages, at least in part, through modulating JAK2/STAT3 pathway.
引文
[1]Martinez FO,Sica A,Mantovani A,et al.Macrophage activation and polarization[J].Front Biosci,2008,13:453-461.
[2]Brown BN,Ratner BD,Goodman SB,et al.Macrophage polarization:an opportunity for improved outcomes in biomaterials and regenerative medicine[J].Biomaterials,2012,33(15):3792-3802.
[3]Geelhaar-Karsch A,Schinnerling K,Conrad K,et al.Evaluation of arginine metabolism for the analysis of M1/M2 macrophage activation in human clinical specimens[J].Inflamm Res,2013,62(9):865-869.
[4]Schwartz Y,Svistelnik AV.Functional phenotypes of macrophages and the M1-M2 polarization concept.Part I.Proinflammatory phenotype[J].Biochemistry(Mosc),2012,77(3):246-260.
[5]Zaki MA,Wada N,Ikeda J,et al.Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma[J].Virchows Arch,2011,459(4):361-366.
[6]Bassaganya-Riera J,Misyak S,Guri AJ,et al.PPAR gamma is highly expressed in F4/80(hi)adipose tissue macrophages and dampens adipose-tissue inflammation[J].Cell Immunol,2009,258(2):138-146.
[7]Bie J,Zhao B,Ghosh S.Atherosclerotic lesion progression is attenuated by reconstitution with bone marrow from macrophage-specific cholesteryl ester hydrolase transgenic mice[J].Am J Physiol Regul Integr Comp Physiol,2011,301(4):967-974.
[8]Spivia W,Magno PS,Le P,et al.Complement protein C1q promotes macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins[J].Inflamm Res,2014,63(10):885-893.
[9]Tacke F,Zimmermann HW.Macrophage heterogeneity in liver injury and fibrosis[J].J Hepatol,2014,60(5):1090-1096.
[10]Duan W,Yang Y,Yan J,et al.The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway[J].Basic Res Cardiol,2012,107(3):263.
[11]Huang WL,Yeh HH,Lin CC,et al.Signal transducer and activator of transcription 3 activation up-regulates interleukin-6autocrine production:a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells[J].Mol Cancer,2010,9:309.
[12]Zhou D,Huang C,Lin Z,et al.Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways[J].Cell Signal,2014,26(2):192-197.
[13]Hu X,Herrero C,Li WP,et al.Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation[J].Nat Immunol,2002,3(9):859-866.
[14]Park HJ,Kim MJ,Ha E,et al.Apoptotic effect of hesperidin through caspase-3 activation in human colon cancer cells,SNU-C4[J].Phytomedicine,2008,15(1-2):147-151.
[15]Li G,Chen MJ,Wang C,et al.Protective effects of hesperidin on concanavalin a-induced hepatic injury in mice[J].Int Immunopharmacol,2014,21(2):406-411.
[16]Wang QQ,Shi JB,Chen C,et al.Hesperetin derivatives:synthesis and anti-inflammatory activity[J].Bioorg Med Chem Lett,2016,26(5):1460-1465.
[17]Jeganathan S,Fiorino C,Naik U,et al.Modulation of osteoclastogenesis with macrophage M1-and M2-inducing stimuli[J].PloS One,2014,9(8):e104498.
[18]Cohen PA,Koski GK,Czerniecki BJ,et al.STAT3-and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34pos cells into tumor-competent dendritic cells[J].Blood,2008,112(5):1832-1843.
[19]Galdiero M,Vitiello M,D'Isanto M,et al.STAT1 and STAT3phosphorylation by porins are independent of JAKs but are dependent on MAPK pathway and plays a role in U937 cells production of interleukin-6[J].Cytokine,2006,36(5-6):218-228.
[20]Jantsch J,Binger KJ,Muller DN,et al.Macrophages in homeostatic immune function[J].Front Physiol,2014,5:146.
[21]Mantovani A,Sozzani S,Locati M,et al.Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes[J].Trends Immunol,2002,23(11):549-555.
[22]Wijesundera KK,Izawa T,Tennakoon AH,et al.M1-and M2-macrophage polarization in rat liver cirrhosis induced by thioacetamide(TAA),focusing on Iba1 and galectin-3[J].Exp Mol Pathol,2014,96(3):382-392.
[23]Patel PN,Yu XM,Jaskula-Sztul R,et al.Hesperetin activates the Notch1 signaling cascade,causes apoptosis,and induces cellular differentiation in anaplastic thyroid cancer[J].Ann Surg Oncol,2014,21;S497-504.
[24]Wilmsen PK,Spada DS,Salvador M.Antioxidant activity of the flavonoid hesperidin in chemical and biological systems[J].J Agr Food Chem,2005,53(12):4757-4761.
[25]Lopez Castejon G,Baroja Mazo A,Pelegrin P.Novel macrophage polarization model:from gene expression to identification of new anti-inflammatory molecules[J].Cell Mol Life Sci,2011,68(18):3095-3107.
[26]Krausgruber T,Blazek K,Smallie T,et al.IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses[J].Net Immunol,2011,12(3):231-238.
[27]Satoh T,Takeuchi O,Vandenbon A,et al.The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection[J].Net Immunol,2010,11(10):936-944.
[28]Zhao W,Lee C,Piganis R,et al.A conserved IFN-alpha receptor tyrosine motif directs the biological response to type IIFNs[J].J Immunol,2008,180(8):5483-5489.
[29]Yang Z,Liu Y,Deng W,et al.Hesperetin attenuates mitochondria-dependent apoptosis in lipopolysaccharide-induced H9C2cardiomyocytes[J].Mol Med Rep,2014,9(5):1941-1946.
[2]Brown BN,Ratner BD,Goodman SB,et al.Macrophage polarization:an opportunity for improved outcomes in biomaterials and regenerative medicine[J].Biomaterials,2012,33(15):3792-3802.
[3]Geelhaar-Karsch A,Schinnerling K,Conrad K,et al.Evaluation of arginine metabolism for the analysis of M1/M2 macrophage activation in human clinical specimens[J].Inflamm Res,2013,62(9):865-869.
[4]Schwartz Y,Svistelnik AV.Functional phenotypes of macrophages and the M1-M2 polarization concept.Part I.Proinflammatory phenotype[J].Biochemistry(Mosc),2012,77(3):246-260.
[5]Zaki MA,Wada N,Ikeda J,et al.Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma[J].Virchows Arch,2011,459(4):361-366.
[6]Bassaganya-Riera J,Misyak S,Guri AJ,et al.PPAR gamma is highly expressed in F4/80(hi)adipose tissue macrophages and dampens adipose-tissue inflammation[J].Cell Immunol,2009,258(2):138-146.
[7]Bie J,Zhao B,Ghosh S.Atherosclerotic lesion progression is attenuated by reconstitution with bone marrow from macrophage-specific cholesteryl ester hydrolase transgenic mice[J].Am J Physiol Regul Integr Comp Physiol,2011,301(4):967-974.
[8]Spivia W,Magno PS,Le P,et al.Complement protein C1q promotes macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins[J].Inflamm Res,2014,63(10):885-893.
[9]Tacke F,Zimmermann HW.Macrophage heterogeneity in liver injury and fibrosis[J].J Hepatol,2014,60(5):1090-1096.
[10]Duan W,Yang Y,Yan J,et al.The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway[J].Basic Res Cardiol,2012,107(3):263.
[11]Huang WL,Yeh HH,Lin CC,et al.Signal transducer and activator of transcription 3 activation up-regulates interleukin-6autocrine production:a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells[J].Mol Cancer,2010,9:309.
[12]Zhou D,Huang C,Lin Z,et al.Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways[J].Cell Signal,2014,26(2):192-197.
[13]Hu X,Herrero C,Li WP,et al.Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation[J].Nat Immunol,2002,3(9):859-866.
[14]Park HJ,Kim MJ,Ha E,et al.Apoptotic effect of hesperidin through caspase-3 activation in human colon cancer cells,SNU-C4[J].Phytomedicine,2008,15(1-2):147-151.
[15]Li G,Chen MJ,Wang C,et al.Protective effects of hesperidin on concanavalin a-induced hepatic injury in mice[J].Int Immunopharmacol,2014,21(2):406-411.
[16]Wang QQ,Shi JB,Chen C,et al.Hesperetin derivatives:synthesis and anti-inflammatory activity[J].Bioorg Med Chem Lett,2016,26(5):1460-1465.
[17]Jeganathan S,Fiorino C,Naik U,et al.Modulation of osteoclastogenesis with macrophage M1-and M2-inducing stimuli[J].PloS One,2014,9(8):e104498.
[18]Cohen PA,Koski GK,Czerniecki BJ,et al.STAT3-and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34pos cells into tumor-competent dendritic cells[J].Blood,2008,112(5):1832-1843.
[19]Galdiero M,Vitiello M,D'Isanto M,et al.STAT1 and STAT3phosphorylation by porins are independent of JAKs but are dependent on MAPK pathway and plays a role in U937 cells production of interleukin-6[J].Cytokine,2006,36(5-6):218-228.
[20]Jantsch J,Binger KJ,Muller DN,et al.Macrophages in homeostatic immune function[J].Front Physiol,2014,5:146.
[21]Mantovani A,Sozzani S,Locati M,et al.Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes[J].Trends Immunol,2002,23(11):549-555.
[22]Wijesundera KK,Izawa T,Tennakoon AH,et al.M1-and M2-macrophage polarization in rat liver cirrhosis induced by thioacetamide(TAA),focusing on Iba1 and galectin-3[J].Exp Mol Pathol,2014,96(3):382-392.
[23]Patel PN,Yu XM,Jaskula-Sztul R,et al.Hesperetin activates the Notch1 signaling cascade,causes apoptosis,and induces cellular differentiation in anaplastic thyroid cancer[J].Ann Surg Oncol,2014,21;S497-504.
[24]Wilmsen PK,Spada DS,Salvador M.Antioxidant activity of the flavonoid hesperidin in chemical and biological systems[J].J Agr Food Chem,2005,53(12):4757-4761.
[25]Lopez Castejon G,Baroja Mazo A,Pelegrin P.Novel macrophage polarization model:from gene expression to identification of new anti-inflammatory molecules[J].Cell Mol Life Sci,2011,68(18):3095-3107.
[26]Krausgruber T,Blazek K,Smallie T,et al.IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses[J].Net Immunol,2011,12(3):231-238.
[27]Satoh T,Takeuchi O,Vandenbon A,et al.The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection[J].Net Immunol,2010,11(10):936-944.
[28]Zhao W,Lee C,Piganis R,et al.A conserved IFN-alpha receptor tyrosine motif directs the biological response to type IIFNs[J].J Immunol,2008,180(8):5483-5489.
[29]Yang Z,Liu Y,Deng W,et al.Hesperetin attenuates mitochondria-dependent apoptosis in lipopolysaccharide-induced H9C2cardiomyocytes[J].Mol Med Rep,2014,9(5):1941-1946.
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