Amelioration of rat adjuvant-induced arthritis by Met-RANTES.

OBJECTIVE CC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met-RANTES, an amino-terminal-modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1alpha (MIP-1alpha; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvant-induced arthritis (AIA) in the rat. METHODS Using immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met-RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA. RESULTS Administration of Met-RANTES as a preventative reduced the severity of joint inflammation. Administration of Met-RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met-RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline-injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met-RANTES inhibited MIP-1alpha and MIP-1beta at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor alpha, interleukin-1beta, macrophage colony-stimulating factor, and RANKL were decreased in joints with AIA in the Met-RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down-regulated in the Met-RANTES group compared with the control group. Functionally, Met-RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint. CONCLUSION The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.

[1]  W. Kuziel,et al.  Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis. , 2004, The Journal of clinical investigation.

[2]  M. Dorf,et al.  RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes , 2002, Glia.

[3]  K. Watanabe,et al.  Rat CINC, a member of the interleukin-8 family, is a neutrophil-specific chemoattractant in vivo. , 1991, Experimental and molecular pathology.

[4]  Craig W. Reynolds,et al.  Distribution of peritoneal macrophage populations after intravenous injection in mice: differential effects of eliciting and activating agents. , 1983, Journal of the Reticuloendothelial Society.

[5]  L. Santambrogio,et al.  RANTES-Induced Chemokine Cascade in Dendritic Cells1 , 2001, The Journal of Immunology.

[6]  Y. Bignon,et al.  Real-time PCR quantification of full-length and exon 11 spliced BRCA1 transcripts in human breast cancer cell lines. , 2000, Biochemical and biophysical research communications.

[7]  M. Kacena,et al.  Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. , 2001, Cytokine & growth factor reviews.

[8]  A. Koch,et al.  Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. , 2001, Arthritis and rheumatism.

[9]  C. Weber,et al.  Met‐RANTES reduces vascular and tubular damage during acute renal transplant rejection: blocking monocyte arrest and recruitment , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  N. Udagawa,et al.  Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. , 1998, Biochemical and biophysical research communications.

[11]  J. Wallace,et al.  The Chemokine RANTES Is a Crucial Mediator of the Progression from Acute to Chronic Colitis in the Rat1 , 2001, The Journal of Immunology.

[12]  M. Oppermann,et al.  Differential Effects of CC Chemokines on CC Chemokine Receptor 5 (CCR5) Phosphorylation and Identification of Phosphorylation Sites on the CCR5 Carboxyl Terminus* , 1999, The Journal of Biological Chemistry.

[13]  S. Georas,et al.  Cutaneous Injection of Human Subjects with Macrophage Inflammatory Protein-1α Induces Significant Recruitment of Neutrophils and Monocytes1 , 2000, The Journal of Immunology.

[14]  G. Rodan,et al.  Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells. , 1999, Experimental cell research.

[15]  G. Haines,et al.  RANTES expression and contribution to monocyte chemotaxis in arthritis. , 1998, Clinical immunology and immunopathology.

[16]  T. Martin,et al.  A combination of osteoclast differentiation factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteoclast formation in vitro. , 1998, Endocrinology.

[17]  Timothy N. C. Wells,et al.  Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  G. Firestein.  Evolving concepts of rheumatoid arthritis , 2003, Nature.

[19]  H. Kondo,et al.  Expression of the chemokine superfamily in rheumatoid arthritis , 1994, Clinical and experimental immunology.

[20]  F. Mach,et al.  Antagonism of RANTES Receptors Reduces Atherosclerotic Plaque Formation in Mice , 2004, Circulation research.

[21]  G. Haines,et al.  Chemokine receptor expression and in vivo signaling pathways in the joints of rats with adjuvant-induced arthritis. , 2003, Arthritis and rheumatism.

[22]  R. Strieter,et al.  Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. , 1998, The Journal of clinical investigation.

[23]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[24]  M. Montjovent,et al.  Extension of Recombinant Human RANTES by the Retention of the Initiating Methionine Produces a Potent Antagonist (*) , 1996, The Journal of Biological Chemistry.

[25]  G. Haines,et al.  Increased synovial expression of transforming growth factor (TGF)-beta receptor endoglin and TGF-beta 1 in rheumatoid arthritis: possible interactions in the pathogenesis of the disease. , 1995, Clinical immunology and immunopathology.

[26]  D. C. Woodruff,et al.  Interleukin-13 gene therapy reduces inflammation, vascularization, and bony destruction in rat adjuvant-induced arthritis. , 2002, Human gene therapy.

[27]  C. Power,et al.  Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. , 1997, Immunology letters.

[28]  S. Gordon,et al.  Adoptive transfer of fluorescence‐labeled cells shows that resident peritonealmacrophages are able to migrate into specialized lymphoid organs and inflammatory sites in the mouse , 1990, European journal of immunology.

[29]  A. Luster,et al.  Chemokines--chemotactic cytokines that mediate inflammation. , 1998, The New England journal of medicine.

[30]  T. Martin,et al.  Tumor Necrosis Factor (cid:97) Stimulates Osteoclast Differentiation by a Mechanism Independent of the ODF/RANKL–RANK Interaction , 2022 .

[31]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[32]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[33]  G. Haines,et al.  IL-4 Adenoviral Gene Therapy Reduces Inflammation, Proinflammatory Cytokines, Vascularization, and Bony Destruction in Rat Adjuvant-Induced Arthritis1 , 2001, The Journal of Immunology.

[34]  D. Gemsa,et al.  Increase of CCR1 and CCR5 expression and enhanced functional response to MIP‐1α during differentiation of human monocytes to macrophages , 2001, Journal of leukocyte biology.

[35]  G. Haines,et al.  Cellular adhesion molecules in rat adjuvant arthritis. , 1996, Arthritis and rheumatism.

[36]  M. Burdick,et al.  Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. , 1994, The Journal of clinical investigation.

[37]  S. Kunkel,et al.  Granulocyte-Macrophage Colony Stimulating Factor Up-Regulates CCR1 in Human Neutrophils1 , 2001, The Journal of Immunology.

[38]  B. Antus,et al.  Early application of Met-RANTES ameliorates chronic allograft nephropathy. , 2002, Kidney international.

[39]  R. Pacifici,et al.  Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. , 2000, The Journal of clinical investigation.

[40]  K Yano,et al.  Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  C. Mackay,et al.  Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. , 1998, Immunology today.