Pyropia yezoensis glycoprotein promotes the M1 to M2 macrophage phenotypic switch via the STAT3 and STAT6 transcription factors

Choi,Jeong-Wook; Kwon,Mi-Jin; Kim,In-Hye; Kim,Young-Min; Lee,Min‑Kyeong; Nam,Taek-Jeong

doi:10.3892/ijmm.2016.2656

Pyropia yezoensis glycoprotein promotes the M1 to M2 macrophage phenotypic switch via the STAT3 and STAT6 transcription factors

Authors:
- Jeong-Wook Choi
- Mi-Jin Kwon
- In-Hye Kim
- Young-Min Kim
- Min‑Kyeong Lee
- Taek-Jeong Nam
View Affiliations

Affiliations: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea, Institute of Fisheries Science, Pukyong National University, Busan 619-911, Republic of Korea
Published online on: June 24, 2016 https://doi.org/10.3892/ijmm.2016.2656
Pages: 666-674

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Macrophage polarization has been well documented. Macrophages can aquire two phenotypes, the pro-inflammatory M1 phenotype, and the anti-inflammatory and wound healing M2 phenotype. The M1 macrophage phenotype has been linked to metabolic disease and is also associated with cancer-related inflammation. Of note, macrophage polarization can be influenced by the extracellular environment. In the current study, we examined the effects of Pyropia yezoensis glycoprotein (PYGP) on M1 to M2 macrophage polarization in lipopolysaccharide (LPS)-stimulated macrophages. RAW 264.7 macrophages stimulated with LPS exhibited an upregulated expression of pro-inflammatory mediators, namely of the M1 markers, nitric oxide (NO), reactive oxygen species (ROS), interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and nitric oxide synthase‑2 (NOS-2). Treatment with PYGP inhibited the production of M1 markers and increased arginase 1 (ARG1), chitinase-like 3 (Chil3; also known as Ym1), resistin like beta (RETNLB; also known as FIZZ1), IL-10, CD163, CD206, peroxisome proliferator-activated receptor γ (PPARγ) and Krüppel-like factor 4 (KLF4) M2 marker gene expression. The signal transducer and activator of transcription (STAT)3 and STAT6 transcription factors were phosphorylated following treatment with PYGP. However, the silencing of STAT3 and STAT6 using siRNA in the macrophages decreased ARG1, Ym1 and FIZZ1 M2 marker gene expression in spite of treatment of PYGP. These findings suggest that PYGP exerts anti-inflammatory effects by regulating the M1 to M2 phenotypic switch through STAT3 and STAT6. Thus, PYGP may have potential for use as a natural remedy for inflammatory diseases.

View Figures

View References

1	Tugal D, Liao X and Jain MK: Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol. 33:1135–1144. 2013. View Article : Google Scholar : PubMed/NCBI
2	Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, Pei H, Chen L, Zheng JJ, Carroll TJ, et al: Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci USA. 107:4194–4199. 2010. View Article : Google Scholar : PubMed/NCBI
3	Nikolic-Paterson DJ and Atkins RC: The role of macrophages in glomerulonephritis. Nephrol Dial Transplant. 16(Suppl 5): 3–7. 2001. View Article : Google Scholar : PubMed/NCBI
4	Aliprantis AO, Diez-Roux G, Mulder LC, Zychlinsky A and Lang RA: Do macrophages kill through apoptosis? Immunol Today. 17:573–576. 1996. View Article : Google Scholar : PubMed/NCBI
5	Murray PJ and Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 11:723–737. 2011. View Article : Google Scholar : PubMed/NCBI
6	Barros MHM, Hauck F, Dreyer JH, Kempkes B and Niedobitek G: Macrophage polarisation: An immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One. 8:e809082013. View Article : Google Scholar : PubMed/NCBI
7	Gordon S and Martinez FO: Alternative activation of macrophages: Mechanism and functions. Immunity. 32:593–604. 2010. View Article : Google Scholar : PubMed/NCBI
8	Kohchi C, Inagawa H, Nishizawa T and Soma G: ROS and innate immunity. Anticancer Res. 29:817–821. 2009.PubMed/NCBI
9	Schroder K, Sweet MJ and Hume DA: Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology. 211:511–524. 2006. View Article : Google Scholar : PubMed/NCBI
10	Martinez FO and Gordon S: The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep. 6:132014. View Article : Google Scholar : PubMed/NCBI
11	Hu X and Ivashkiv LB: Cross-regulation of signaling pathways by interferon-γ: Implications for immune responses and autoimmune diseases. Immunity. 31:539–550. 2009. View Article : Google Scholar : PubMed/NCBI
12	Mantovani A, Biswas SK, Galdiero MR, Sica A and Locati M: Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 229:176–185. 2013. View Article : Google Scholar
13	Mantovani A, Garlanda C and Locati M: Macrophage diversity and polarization in atherosclerosis: A question of balance. Arterioscler Thromb Vasc Biol. 29:1419–1423. 2009. View Article : Google Scholar : PubMed/NCBI
14	Kim SC, Lee JR and Park SJ: Porphyra tenera induces apoptosis of oral cancer cells. Kor J Herbology. 30:25–30. 2015.
15	Kim YM, In JP and Park JH: Angiotensin I converting enzyme (ACE) inhibitory activities of laver (Porphyra tenera) protein hydrolysates. Prev Nutr Food Sci. 18:11–18. 2005.
16	Shin ES, Hwang HJ, Kim IH and Nam TJ: A glycoprotein from Porphyra yezoensis produces anti-inflammatory effects in liposaccharide-stimulated macrophages via the TLR4 signaling pathway. Int J Mol Med. 28:809–815. 2011.PubMed/NCBI
17	Hwang HJ, Kwon MJ, Kim IH and Nam TJ: Chemoprotective effects of a protein from the red algae Porphyra yezoensis on acetaminophen-induced liver injury in rats. Phytother Res. 22:1149–1153. 2008. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar
19	Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, Mahabeleshwar GH, Dalmas E, Venteclef N, et al: Krüppel-like factor 4 regulates macrophage polarization. J Clin Invest. 121:2736–2749. 2011. View Article : Google Scholar : PubMed/NCBI
20	Szanto A, Balint BL, Nagy ZS, Barta E, Dezso B, Pap A, Szeles L, Poliska S, Oros M, Evans RM, et al: STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells. Immunity. 33:699–712. 2010. View Article : Google Scholar : PubMed/NCBI
21	Labonte AC, Tosello-Trampont AC and Hahn YS: The role of macrophage polarization in infectious and inflammatory diseases. Mol Cells. 37:275–285. 2014. View Article : Google Scholar : PubMed/NCBI
22	Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M and Udalova IA: IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 12:231–238. 2011. View Article : Google Scholar : PubMed/NCBI
23	Lawrence T and Natoli G: Transcriptional regulation of macrophage polarization: Enabling diversity with identity. Nat Rev Immunol. 11:750–761. 2011. View Article : Google Scholar : PubMed/NCBI
24	Biswas SK and Mantovani A: Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat Immunol. 11:889–896. 2010. View Article : Google Scholar : PubMed/NCBI
25	Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, de Waal-Malefyt R and Ottenhoff TH: Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA. 101:4560–4565. 2004. View Article : Google Scholar : PubMed/NCBI
26	Agard M, Asakrah S and Morici LA: PGE(2) suppression of innate immunity during mucosal bacterial infection. Front Cell Infect Microbiol. 3:452013. View Article : Google Scholar : PubMed/NCBI
27	Kilbourn RG and Griffith OW: Overproduction of nitric oxide in cytokine-mediated and septic shock. J Natl Cancer Inst. 84:827–831. 1992. View Article : Google Scholar : PubMed/NCBI
28	Hard GC: Some biochemical aspects of the immune macrophage. Br J Exp Pathol. 51:97–105. 1970.PubMed/NCBI
29	Galván-Peña S and O'Neill LA: Metabolic reprograming in macrophage polarization. Front Immunol. 5:4202014.PubMed/NCBI
30	West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS and Ghosh S: TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 472:476–480. 2011. View Article : Google Scholar : PubMed/NCBI
31	Jacobson MD: Reactive oxygen species and programmed cell death. Trends Biochem Sci. 21:83–86. 1996. View Article : Google Scholar : PubMed/NCBI
32	Corraliza IM, Soler G, Eichmann K and Modolell M: Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. Biochem Biophys Res Commun. 206:667–673. 1995. View Article : Google Scholar : PubMed/NCBI
33	Munder M, Eichmann K and Modolell M: Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: Competitive regulation by CD4⁺ T cells correlates with Th1/Th2 phenotype. J Immunol. 160:5347–5354. 1998.PubMed/NCBI
34	Scotton CJ, Martinez FO, Smelt MJ, Sironi M, Locati M, Mantovani A and Sozzani S: Transcriptional profiling reveals complex regulation of the monocyte IL-1 β system by IL-13. J Immunol. 174:834–845. 2005. View Article : Google Scholar : PubMed/NCBI
35	Raes G, De Baetselier P, Noël W, Beschin A, Brombacher F and Hassanzadeh Gh G: Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol. 71:597–602. 2002.PubMed/NCBI
36	Ricote M, Welch JS and Glass CK: Regulation of macrophage gene expression by the peroxisome proliferator-activated receptor-γ. Horm Res. 54:275–280. 2000. View Article : Google Scholar
37	Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A and Locati M: The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25:677–686. 2004. View Article : Google Scholar : PubMed/NCBI
38	Brown BN, Londono R, Tottey S, Zhang L, Kukla KA, Wolf MT, Daly KA, Reing JE and Badylak SF: Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater. 8:978–987. 2012. View Article : Google Scholar
39	Lau SK, Chu PG and Weiss LM: CD163: A specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol. 122:794–801. 2004. View Article : Google Scholar : PubMed/NCBI
40	Chen Z, Wu C, Gu W, Klein T, Crawford R and Xiao Y: Osteogenic differentiation of bone marrow MSCs by β-tricalcium phosphate stimulating macrophages via BMP2 signalling pathway. Biomaterials. 35:1507–1518. 2014. View Article : Google Scholar
41	Lee AS, Jung YJ, Kim D, Nguyen-Thanh T, Kang KP, Lee S, Park SK and Kim W: SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages. Biochem Biophys Res Commun. 450:1363–1369. 2014. View Article : Google Scholar : PubMed/NCBI
42	Lopez-Castejón G, Baroja-Mazo A and Pelegrín P: Novel macrophage polarization model: From gene expression to identification of new anti-inflammatory molecules. Cell Mol Life Sci. 68:3095–3107. 2011. View Article : Google Scholar
43	Wang N, Liang H and Zen K: Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol. 5:6142014. View Article : Google Scholar : PubMed/NCBI
44	Murray PJ: Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol. 6:379–386. 2006. View Article : Google Scholar : PubMed/NCBI
45	Mandal P, Pratt BT, Barnes M, McMullen MR and Nagy LE: Molecular mechanism for adiponectin-dependent M2 macrophage polarization: Link between the metabolic and innate immune activity of full-length adiponectin. J Biol Chem. 286:13460–13469. 2011. View Article : Google Scholar : PubMed/NCBI
46	MacKinnon AC, Farnworth SL, Hodkinson PS, Henderson NC, Atkinson KM, Leffler H, Nilsson UJ, Haslett C, Forbes SJ and Sethi T: Regulation of alternative macrophage activation by galectin-3. J Immunol. 180:2650–2658. 2008. View Article : Google Scholar : PubMed/NCBI