**7. References**


Although ADM may have anti-inflammatory properties, the effect of ADM on IL-6 production in inflamed synovial tissue might be an undesirable adverse effect in RA therapy. Further research is necessary to investigate the drug effects, the time of administration, and the dosage schedules of intra-articular injection of ADM in the

The authors would like to thank Prof. Kazuo Kitamura for his helpful discussion, Prof. Yujiro Asada for the offer of sample in the immunohistochemical study, and Ms Mariko

Arend WP & Dayer JM. (1995) Inhibition of the production and effects of interleukin-1 and

Asada Y, Hara S, Marutsuka K, Kitamura K, Tsuji T, Sakata J, Sato Y, Kisanuki A, Eto T &

Clementi G, Caruso A, Cutuli VM, Prato A, Mangano NG, Amico-Roxas M. (1999)

Chosa E, Hamada H, Kitamura K, Eto T & Tajima N.(2003) Increased plasma and joint tissue

Chu CQ, Field M, Feldmann M & Maini RN. (1991) Localization of tumor necrosis factor

Clauss M, Sunderkötter C, Sveinbjörnsson B, Hippenstiel S, Willuweit A, Marino M, Haas E,

Clegg DO & Ward JR. (1987) Diagnostic criteria in rheumatoid arthritis. *Scand J Rheumatol* 

Consden R, Doble A, Glynn LE & Nind AP. (1971) Production of a chronic arthritis with

Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, Brennan FM, Walker

Elsasser TH & Kahl S. (2002) Adrenomedullin has multiple roles in disease stress:

tumor necrosis factor alpha in rheumatoid arthritis. *Arthritis Rheum.* Vol. 38, pp.

Sumiyoshi A. (1999) Novel distribution of adrenomedullin-immunoreactive cells in

Antiinflammatory activity of adrenomedullin in the acetic acid peritonitis in rats.

adrenomedullin concentrations in patients with rheumatoid arthritis compared to

alpha in synovial tissues and at the cartilage–pannus junction in patients with

Seljelid R, Scheurich P, Suttorp N, Grell M & Risau W. (2001)A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular

ovalbumin. Its retention in the rabbit knee joint. *Ann Rheum Dis.* Vol. 30, pp. 307–

J, Bijl H, Ghrayeb J, et al. (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. *Arthritis Rheum.* Vol. 36, pp.

development and remission of the inflammatory response. *Microsc Res Tech* Apr 15

Tokashiki for technical support in measurement of the plasma AM concentration.

human tissues. *Histochem Cell Biol*, Vol. 112, pp. 185-191.

those with osteoarthritis. *J Rheumatol.* Vol. 30, pp. 2553–2556.

rheumatoid arthritis. *Arthritis Rheum.* Vol. 34, pp. 1125–1132.

permeability. *Blood.* Vol. 97, pp. 1321–29.

*Suppl*. Vol. 65, pp. 3-11. Review

treatment of RA.

**7. References** 

**6. Acknowledgment** 

151–160

315.

1681–1690.

Vol. 57. pp. 120-9.

*Life Sci* Vol.65, pp. 203-8.


Role of Adrenomedullin in Patients with Rheumatoid Arthritis 193

Nishimoto N, Ito A, Ono M, Tagoh H, Matsumoto T, Tomita T, Ochi T & Yoshizaki K. (2000)

Nanke Y, Kotake S, Yonemoto K, Saito S, Tomatsu T, Kamatani N. (2003)

Nishimoto N, Kishimoto T & Yoshizaki K. (2000) Anti-interleukin 6 receptor antibody treatment in rheumatic disease. *Ann Rheum Dis.* Vol. 59 (Suppl 1), pp. i21–i27. Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J,

Okura T, Marutsuka K, Hamada H, Sekimoto T, Fukushima T, Asada Y, Kitamura K,

Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. (1990) Correlations

Tilg H, Dinarello CA & Mier JW. (1997) IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. *Immunol Today.* Vol. 18, pp. 428–432. Ueda S, Nishio K, Minamino N, Kubo A, Akai Y, Kangawa K, Matsuo H, Fujimura Y,

Uemura T, Kato J, Kuwasako K, Kitamura K, Kangawa K & Eto T. (2002) Aldosterone

Wong LY, Cheung BM, Li YY & Tang F. (2005) Adrenomedullin is both proinflammatory

Wu R, Zhou M & Wang P. (2003) Adrenomedullin and adrenomedullin binding protein-1

Yang S, Zhou M, Fowler DE & Wang P. (2002) Mechanisms of the beneficial effect of

controlled trial. *Arthritis Rheum.* Vol. 50, pp. 1761–1769.

syndrome. *Am J Respir Crit Care Med* Vol. 160, pp. 132-6.

187–193.

Epub

*Blood.* Vol. 75, pp. 40–47.

20 (6), pp. 1209-14

112, pp. 19–26.

2735.

*Endocrinology.* Vol. 146, pp. 1321–1327.

62(1), pp. 82-3.

IL-6 inhibits the proliferation of fibroblastic synovial cells from rheumatoid arthritis patients in the presence of soluble IL-6 receptor. *Int Immunol.* Vol. 12, pp.

Adrenomedullin in synovial fluids from patients with rheumatoid arthritis inhibits interleukin 6 production from synoviocytes. *Ann Rheum Dis.* Jan, Vol.

Azuma J & Kishimoto T. (2004) Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-

Chosa E. (2008) Therapeutic efficacy of intra-articular adrenomedullin injection in antigen-induced arthritis in rabbits. Arthritis Res Ther. Vol. 10(6), pp133.

and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF.

Yoshioka A, Masui K, Doi N, Murao Y & Miyamoto S. (1999) Increased plasma levels of adrenomedullin in patients with systemic inflammatory response

augments adrenomedullin production without stimulating pro-adrenomedullin Nterminal 20 peptide secretion in vascular smooth muscle cells. *J. Hypertension* Vol.

and antiinflammatory: its effects on gene expression and secretion of cytokines and macrophage migration inhibitory factor in NR8383 macrophage cell line.

downregulate TNF-α in macrophage cell line and rat Kupffer cells. *Regul Pept.* Vol.

adrenomedullin and adrenomedullin-binding protein-1 in sepsis: downregulation of proinflammatory cytokines. *Crit Care Med.* Vol. 30, pp. 2729–


Nanki T, Nagasaka K, Hayashida K, Saita Y and Miyasaka N.(2001) Chemokines regulate

Kellgren JH & Lawrence JL. (1958) Osteoarthritis and disc degeneration in an urban

Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S,Matsuo H & Eto T (1993)

pheochromocytoma. Biochem Biophys Res Commun Vol. 192, pp. 553–560 Kitamura K, Ichiki Y, Tanaka M, Kawamoto M, Emura J, Sakakibara S, Kangawa K, Matsuo

Kita T, Kitamura K, Hashida S, Morishita K & Eto T. (2003) Plasma adrenomedullin is

Kobayashi K, Kitamura K, Hirayama N, Date H, Kashiwagi T, Ikushima I, Hanada Y,

Kubo A, Minamino N, Isumi Y, Katafuchi T, Kangawa K, Dohi K & Matsuo H. ( 1998)

Leask A & Abraham DJ. (2004) TGF-β signaling and the fibrotic response. *FASEB J* Vol. 18,

Miyashita K, Itoh H, Arai H, Suganami T, Sawada N, Fukunaga Y, Sone M, Yamahara K,

Mizuhara H, O'Neill E, Seki N, Ogawa T, Kusunoki C, Otsuka K, Satoh S, Niwa M, Senoh H

Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL,

Nishikimi T, Saito Y, Kitamura K, Ishimitsu T, Eto T, Kangawa K, Matsuo H, Omae T &

receptor (p75)-Fc fusion protein. *N Engl J Med.* Vol. 337, pp. 141–147. Nakamura R, Kato J, Kitamura K, Onitsuka H, Imamura T, Cao Y, Marutsuka K, Asada Y,

rheumatoid arthritis *J Immunol*. Nov 1; Vol. 167(9):5381-5

population. *Ann Rheum Dis*. Vol. 17, pp. 388-97.

Vol. 341, pp. 288-90.

131, pp. 676–680.

pp. 816–827.

1529–1537.

Vol. 110, pp. 426–431.

*Hypertens Res.* Vol. 26, pp. 887–893

*J Biol Chem.* Vol. 273, pp. 16730–16738.

potential. *Endocrinology.* Vol.147, pp. 1642–1653.

heart failure. *J Am Coll Cardiol.* Vol. 26, pp. 1424-31.

IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with

Adrenomedullin: a novel hypotensive peptide isolated from human

H & Eto T. (1994) Immunoreactive adrenomedullin in human plasma. FEBS Lett

closely correlated with pulse wave velocity in middle-aged and elderly patients.

Nagatomo Y, Takenaga M, Ishikawa T, Imamura T, Koiwaya Y & Eto T. (1996) Increased plasma adrenomedullin in acute myocardial infarction. *Am Heart J.* Vol.

Production of adrenomedullin in macrophage cell line and peritoneal macrophage.

Yurugi-Kobayashi T, Park K, Oyamada N, Sawada N, Taura D, Tsujimoto H, Chao TH, Tamura N, Mukoyama M & Nakao K. (2006) The neuroprotective and vasculoneuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic

& Fujiwara H. (1994) T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. *J Exp Med.* Vol.179, pp.

Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB & Blosch CM. (1997) Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor

Kangawa K & Eto T. (2004) Adrenomedullin administration immediately after myocardial infarction ameliorates progression of heart failure in rats. *Circulation.*

Matsuoka H. (1995) Increased plasma levels of adrenomedullin in patients with


**10** 

**Targeting the Metabolism and Receptors** 

Sphingolipids belong to a major class of lipids that are ubiquitously synthesized by eukaryotic cells and are characterized by their sphingoid backbone and primary structural roles in membrane formation. Over the past two decades, sphingolipids have emerged as a source of important signalling molecules in addition to their structural functions (Merrill et al., 1997). In particular, sphingosine-1-phosphate (S1P), is a unique signalling molecule that has the ability to act as an intracellular second messenger, as well as an extracellular stimulus through specific G protein-coupled receptor (GPCRs) (Pyne and Pyne, 2000; Spiegel and Milstien, 2003; Van Brocklyn et al., 1998). S1P has been shown to mediate a variety of fundamental biological processes including cell proliferation, migration, invasion, angiogenesis, vascular maturation and lymphocyte trafficking. The intracellular level of S1P is tightly regulated by the equilibrium between its synthesis by sphingosine kinases (SphKs) and its degradation by S1P phosphatases (SPPs) and S1P lyase (SPL) (Saba and Hla, 2004). Activation of SphKs by a variety of agonists, including growth factors, cytokines and hormones, increases intracellular S1P. Once generated, S1P can either act intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signalling through S1P receptors expressed on the surface of the same cell or nearby cells in autocrine and/or paracrine manners (Alvarez et al., 2007). Many of the biological effects of S1P are mediated by its binding to and activation of its specific receptors S1P1–S1P5 (Ishii et al., 2004). Alterations in S1P signalling, as well as in the enzymes involved in its synthesis and metabolism, have been observed in many types of pathological situations such as

The role played by S1P in the autoimmune disease rheumatoid arthritis (RA) has recently emerged. Activated SphK and elevated levels of S1P have been detected in the synovium and synovial fluids of patients with RA, respectively (Kamada et al., 2009; Kitano et al., 2006; Lai et al., 2008). In addition, exogenously applied S1P in cultured synovial fibroblasts from RA patients causes cell migration, production of cytokines/chemokines, expression of cyclooxygenase-2 and prostaglandins, as well as cell proliferation and survival (Kitano et al., 2006; Zhao et al., 2008). These results suggest a biological function for the SphK/S1P/S1P receptor (S1PR) axes in RA disease progression. In this review we summarize the current understanding of how S1P metabolism and signalling impact the biology of inflammation in

**1. Introduction** 

angiogenesis, metastasis, and autoimmunity.

 **of Sphingosine-1-Phosphate for the** 

 **Treatment of Rheumatoid Arthritis** 

Sylvain G. Bourgoin, Chenqi Zhao

and Maria J. Fernandes

*Laval University* 

*Canada* 

