Skip to main content

Advertisement

SpringerLink
Log in

Phosphatidylserine-Containing Liposomes: Potential Pharmacological Interventions Against Inflammatory and Immune Diseases Through the Production of Prostaglandin E2 After Uptake by Myeloid Derived Phagocytes

  • REVIEW
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Phosphatidylserine (PS), which is normally located on the inner leaflet of the plasma membrane, translocates to the outer leaflet at the early stage of apoptosis. The PS externalization provides a signal for phagocytes to initiate uptake of apoptotic cells. After phagocytosis of apoptotic cells, phagocytes induce the secretion of anti-inflammatory mediators including prostaglandin E2 (PGE2). PS-containing liposomes (PSLs) can mimic the effects of apoptotic cells on phagocytes to induce the secretion of PGE2. PSLs induce the PGE2 secretion from microglia without induction of either cyclooxygenase (COX)-2 or microsomal prostaglandin E synthase (mPGES)-1. PSLs are found to rather utilize COX-1/mPGES-2 system to produce PGE2 secretion and then shift microglia and macrophages from pro- to anti-inflammatory phenotype by an autocrine action of PGE2. Moreover, PSLs inhibit the maturation of dendritic cells and osteoclast precursors. Therefore, PSLs will be potential pharmacological interventions for inflammatory and immune diseases through feedback mechanism utilizing PGE2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aloisi F, De Simone R, Columba-Cabezas S et al (1999) Opposite effects of interferon-gamma and prostaglandin E2 on tumor necrosis factor and interleukin-10 production in microglia: a regulatory loop controlling microglia pro- and anti-inflammatory activities. J Neurosci Res 56:571–580

    Article  PubMed  CAS  Google Scholar 

  • Athanasou NA, Quinn J (1990) Immunophenotypic differences between osteoclasts and macrophage polykaryons: immunohistological distinction and implications for osteoclast ontogeny and function. J Clin Pathol 43:997–1003

    Article  PubMed  CAS  Google Scholar 

  • Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  PubMed  CAS  Google Scholar 

  • Boabaid F, Cerri PS, Katchburian E (2001) Apoptotic bone cells may be engulfed by osteoclasts during alveolar bone resorption in young rats. Tissue Cell 33:318–325

    Article  PubMed  CAS  Google Scholar 

  • Cerri PS, Boabaid F, Katchburian E (2003) Combined TUNEL and TRAP methods suggest that apoptotic bone cells are inside vacuoles of alveolar bone osteoclasts in young rats. J Periodontal Res 38:223–226

    Article  PubMed  CAS  Google Scholar 

  • Chae BS, Shin TY, Kim DK et al (2008) Prostaglandin E2-mediated dysregulation of proinflammatory cytokine production in pristane-induced lupus mice. Arch Pharm Res 31:503–510

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Doffek K, Sugg SL et al (2004) Phosphatidylserine regulates the maturation of human dendritic cells. J Immunol 173:2985–2994

    PubMed  CAS  Google Scholar 

  • Conconi MT, Tommasini M, Baiguera S et al (2002) Effects of prostaglandin E1 and E2 on the growth and differentiation of osteoblast-like cells cultured in vitro. Int J Mol Med 10:451–456

    PubMed  CAS  Google Scholar 

  • De SR, Ajmone-Cat MA, Nicolini A et al (2002) Expression of phosphatidylserine receptor and down-regulation of pro-inflammatory molecule production by its natural ligand in rat microglial cultures. J Neuropathol Exp Neurol 61:237–244

    PubMed  Google Scholar 

  • Dieter P, Hempel U, Kamionka S et al (1999) Prostaglandin E2 affects differently the release of inflammatory mediators from resident macrophages by LPS and muramyl tripeptides. Mediators Inflamm 8:295–303

    Article  PubMed  CAS  Google Scholar 

  • Fadok VA, Bratton DL, Konowal A et al (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Invest 101:890–898

    Article  PubMed  CAS  Google Scholar 

  • Fennekohl A, Sugimoto Y, Segi E et al (2002) Contribution of the two Gs-coupled PGE2-receptors EP2-receptor and EP4-receptor to the inhibition by PGE2 of the LPS-induced TNF-alpha-formation in Kupffer cells from EP2- or EP4-receptor-deficient mice. Pivotal role for the EP4-receptor in wild type Kupffer cells. J Hepatol 36:328–334

    Article  PubMed  CAS  Google Scholar 

  • Flanagan AM, Chambers TJ (1992) Stimulation of bone nodule formation in vitro by prostaglandin E1 and E2. Endocrinology 130:443–448

    Article  PubMed  CAS  Google Scholar 

  • Fujino H, Salvi S, Regan JW (2005) Differential regulation of phosphorylation of the cAMP response element-binding protein after activation of EP2 and EP4 prostanoid receptors by prostaglandin E2. Mol Pharmacol 68:251–259

    PubMed  CAS  Google Scholar 

  • Gao Q, Xu M, Alander CB et al (2009) Effects of prostaglandin E2 on bone in mice in vivo. Prostaglandins Other Lipid Mediat 89:20–25

    Article  PubMed  CAS  Google Scholar 

  • Hakeda Y, Nakatani Y, Kurihara N et al (1985) Prostaglandin E2 stimulates collagen and non-collagen protein synthesis and prolyl hydroxylase activity in osteoblastic clone MC3T3-E1 cells. Biochem Biophys Res Commun 126:340–345

    Article  PubMed  CAS  Google Scholar 

  • Harizi H, Norbert G (2004) Inhibition of IL-6, TNF-α, and cyclooxygenase-2 protein expression by prostaglandin E2-induced IL-10 in bone marrow-derived dendritic cells. Cell Immunol 228:99–109

    Article  PubMed  Google Scholar 

  • Harizi H, Juzan M, Pitard V et al (2002) Cyclooxygenase-2-issued prostaglandin E2 enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. J Immunol 168:2255–2263

    PubMed  CAS  Google Scholar 

  • Harizi H, Grosset C, Gualde N et al (2003) Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes. J Leukoc Biol 73:756–763

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann PR, deCathelineau AM, Ogden CA (2001) Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155:649–659

    Article  PubMed  CAS  Google Scholar 

  • Hurley MM, Lee SK, Raisz LG et al (1998) Basic fibroblast growth factor induces osteoclast formation in murine bone marrow cultures. Bone 22:309–316

    Article  PubMed  CAS  Google Scholar 

  • Huynh ML, Fadok VA, Henson PM (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation. J Clin Invest 109:41–50

    PubMed  CAS  Google Scholar 

  • Itonaga I, Sabokbar A, Neale SD et al (1999) 1,25-Dihydroxyvitamin D3 and prostaglandin E2 act directly on circulating human osteoclast precursors. Biochem Biophys Res Commun 264:590–595

    Article  PubMed  CAS  Google Scholar 

  • Iyoda T, Shimoyama S, Liu K et al (2002) The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 195:1289–1302

    Article  PubMed  CAS  Google Scholar 

  • Jing H, Vassiliou E, Ganea D (2003) Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells. J Leukoc Biol 74:868–879

    Article  PubMed  CAS  Google Scholar 

  • Kim EJ, Kwon KJ, Park JY et al (2002) Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation. J Neurosci Res 70:97–107

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi Y, Take I, Yamashita T et al (2005) Prostaglandin E2 receptors EP2 and EP4 are down-regulated during differentiation of mouse osteoclasts from their precursors. J Biol Chem 280:24035–24042

    Article  PubMed  CAS  Google Scholar 

  • Kong YY, Yoshida H, Sarosi I et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323

    Article  PubMed  CAS  Google Scholar 

  • Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    Article  PubMed  CAS  Google Scholar 

  • Li J, Sarosi I, Yan XQ et al (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97:1566–1571

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7

    Article  PubMed  CAS  Google Scholar 

  • Mittal J, Dogra N, Vohra H et al (2001) Effects of prostaglandin E2 and nitric oxide inhibitors on the expression of interleukin-10, interleukin-12 and MHC class-II molecules in Mycobacterium microti-infected and interferon-gamma-treated mouse peritoneal macrophages. Folia Microbiol 46:259–264

    Article  CAS  Google Scholar 

  • Miyamoto T, Phneda O, Arai F et al (2001) Bifurcation of osteoclasts and dendritic cells from common progenitors. Blood 98:2544–2554

    Article  PubMed  CAS  Google Scholar 

  • Murakami M, Nakatani Y, Kuwata H et al (2000) Cellular components that functionally interact with signaling phospholipase A2s. Biochim Biophys Acta 1488:159–166

    PubMed  CAS  Google Scholar 

  • Murakami M, Nakashima K, Kamei D et al (2003) Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J Biol Chem 278:37937–37947

    Article  PubMed  CAS  Google Scholar 

  • Nagata T, Kaho K, Nishikawa S et al (1994) Effect of prostaglandin E2 on mineralization of bone nodules formed by fetal rat calvarial cells. Calcif Tissue Int 55:451–457

    Article  PubMed  CAS  Google Scholar 

  • Norgauer J, Ibig Y, Gmeiner D et al (2003) Prostaglandin E2 synthesis in human monocyte-derived dendritic cells. Int J Mol Med 12:83–86

    PubMed  CAS  Google Scholar 

  • Ogawa M, Suzuki J, Kosuge H et al (2009) The mechanism of anti-inflammatory effects of prostaglandin E2 receptor 4 activation in murine cardiac transplantation. Transplantation 87:1645–1653

    Article  PubMed  CAS  Google Scholar 

  • Okada Y, Lorenzo JA, Freeman AM et al (2000) Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture. J Clin Invest 105:823–832

    Article  PubMed  CAS  Google Scholar 

  • Otsuka M, Tsuchiya S, Aramaki Y (2004) Involvement of ERK, a MAP kinase, in the production of TGF-beta by macrophages treated with liposomes composed of phosphatidylserine. Biochem Biophys Res Commun 324:1400–1405

    Article  PubMed  CAS  Google Scholar 

  • Perry VH, Gordon S (1988) Macrophages and microglia in the nervous system. Trends Neurosci 11:273–277

    Article  PubMed  CAS  Google Scholar 

  • Petrova TV, Akama KT, Van Eldik LJ (1999) Selective modulation of BV-2 microglial activation by prostaglandin E2. Differential effects on endotoxin-stimulated cytokine induction. J Biol Chem 274:28823–28827

    Article  PubMed  CAS  Google Scholar 

  • Roux S, Pichaud F, Qinn J et al (1997) Effects of prostaglandins on human hematopoietic osteoclast precursors. Endocrinology 138:1476–1482

    Article  PubMed  CAS  Google Scholar 

  • Rouzer CA, Kingsley PJ, Wang H et al (2004) Cyclooxygenase-1-dependent prostaglandin synthesis modulates tumor necrosis factor-alpha secretion in lipopolysaccharide-challenged murine resident peritoneal macrophages. J Biol Chem 279:34256–34268

    Article  PubMed  CAS  Google Scholar 

  • Shi D, Fu M, Fan P et al (2007) Artificial phosphatidylserine liposome mimics apoptotic cells in inhibiting maturation and immunostimulatory function of murine myeloid dendritic cells in response to 1-chloro-2,4-dinitrobenze in vitro. Arch Dermatol Res 299:327–336

    Article  PubMed  CAS  Google Scholar 

  • Shibata Y, Nishiyama A, Ohata H et al (2005) Differential effects of IL-10 on prostaglandin H synthase-2 expression and prostaglandin E2 biosynthesis between spleen and bone marrow macrophages. J Leukoc Biol 77:544–551

    Article  PubMed  CAS  Google Scholar 

  • Spaggiari GM, Abdelrazik H, Becchetti F et al (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113:6576–6583

    Article  PubMed  CAS  Google Scholar 

  • Stafford JB, Marnett LJ (2008) Prostaglandin E2 inhibits tumor necrosis factor-alpha RNA through PKA type I. Biochem Biophys Res Commun 366:104–109

    Article  PubMed  CAS  Google Scholar 

  • Steinman RM, Turley S, Mellman I et al (2000) The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 191:411–416

    Article  PubMed  CAS  Google Scholar 

  • Suk K, Yeou Kim S, Kim H (2001) Regulation of IL-18 production by IFN-γ and PGE2 in mouse microglial cells: involvement of NF-κB pathway in the regulatory processes. Immunol Lett 77:79–85

    Article  PubMed  CAS  Google Scholar 

  • Takayama K, García-Cardena G, Sukhova GK et al (2002) Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem 277:44147–44154

    Article  PubMed  CAS  Google Scholar 

  • Take I, Kobayashi Y, Yamamoto Y et al (2005) Prostaglandin E2 strongly inhibits human osteoclast formation. Endocrinology 146:5204–5014

    Google Scholar 

  • Tanaka M, Sakai A, Uchida S et al (2004) Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats. Bone 34:940–948

    Article  PubMed  CAS  Google Scholar 

  • Teitelbaum SL, Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4:638–649

    Article  PubMed  CAS  Google Scholar 

  • Tian XY, Zhang Q, Zhao R et al (2008) Continuous PGE2 leads to net bone loss while intermittent PGE2 leads to net bone gain in lumbar vertebral bodies of adult female rats. Bone 42:914–920

    Article  PubMed  CAS  Google Scholar 

  • van der Pouw Kraan TC, van Lier RA, Aarden LA (1995) PGE2 and the immune response. A central role for prostaglandin E2 in downregulating the inflammatory immune response. Mol Med Today 1:61

    Article  PubMed  CAS  Google Scholar 

  • Vassiliou E, Jing H, Ganea D (2003) Prostaglandin E2 inhibits TNF production in murine bone marrow-derived dendritic cells. Cell Immunol 223:120–132

    Article  PubMed  CAS  Google Scholar 

  • Wu Z, Nakanishi H (2010) Regulation of myeloid derived phagocytes by phosphatidylserine-containing liposomes: possible involvement of prostaglandin E2 and potential therapeutic application. In: Goodwin GM (ed) Prostaglandins: biochemistry, functions, types and roles. Nova Science Publishers, Inc., New York, pp 81–92

    Google Scholar 

  • Wu X, Zeng LH, Taniguchi T (2007) Activation of PKA and phosphorylation of sodium-dependent vitamin C transporter 2 by prostaglandin E2 promote osteoblast-like differentiation in MC3T3-E1 cells. Cell Death Differ 14:1792–1801

    Article  PubMed  Google Scholar 

  • Wu Z, Ma HM, Kukita T et al (2010) Phosphatidylserine-containing liposomes inhibit the differentiation of osteoclasts and trabecular bone loss. J Immunol 184:3191–3201

    Article  PubMed  CAS  Google Scholar 

  • Yoshida K, Oida H, Kobayashi T et al (2002) Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc Natl Acad Sci USA 99:4580–4585

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Fujii S, Wu Z et al (2006) Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E2 production by microglia. J Neuroimmunol 172:112–120

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Studies conducted in our laboratories were supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (No. 20592174 to Zhou Wu and No. 20390472 to Hiroshi Nakanishi).

Author information

Authors and Affiliations

  1. Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan

    Zhou Wu & Hiroshi Nakanishi

Authors
  1. Zhou Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhou Wu or Hiroshi Nakanishi.

About this article

Cite this article

Wu, Z., Nakanishi, H. Phosphatidylserine-Containing Liposomes: Potential Pharmacological Interventions Against Inflammatory and Immune Diseases Through the Production of Prostaglandin E2 After Uptake by Myeloid Derived Phagocytes. Arch. Immunol. Ther. Exp. 59, 195–201 (2011). https://doi.org/10.1007/s00005-011-0123-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-011-0123-4

Keywords

Search

Navigation