A novel anti-inflammatory role for simvastatin in inflammatory arthritis

Bernard P. Leung, Naveed Sattar, Anne Crilly, Morag Prach, David W. McCarey, Helen Payne, Rajan Madhok, Carol Campbell, J. Alastair Gracie, Foo Y. Liew, Iain B. McInnes

Research output: Contribution to journalArticle

Abstract

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-γ release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)3 reductase inhibitors (statins) have been unequivocally shown to reduce cardiovascular morbidity and mortality (1, 2). Although such clinical benefits are mediated in part through lipid modulation, recent studies demonstrate broader properties for statins, particularly in modifying inflammatory pathways ongoing within the atherosclerotic lesion (3). The molecular mechanisms subserving such immunomodulatory activities remain unclear. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid (MVA) during cholesterol synthesis. Downstream metabolites, including geranylgeranyl pyrophosphate and farnesyl pyrophosphate regulate prenylation within several critical signaling pathways (4). Statins inhibit IFN-γ-inducible macrophage MHC class II expression via class II transactivator suppression (5) and activate peroxisome proliferator-activated receptor-α via inhibition of Rho-dependent pathways (6). Moreover, some statins (e.g., lovastatin, simvastatin) may modulate T cell costimulation through direct effects on LFA-1/ICAM-1 interactions, dependent upon recognition of a novel statin binding site on β2integrins (7). These properties indicate that statins might modulate functional maturation of T lymphocytes.Following Ag exposure, T lymphocytes mature to different functional phenotypes distinguished on the pattern of cytokine production. Th1 responses, characterized by IFN-γ release, are critical to the development and course of several important autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (8), and have a postulated role in vascular wall inflammation (9, 10). However, definitive proof that statins can modify Th1/Th2 responses with immunopathologic consequence in vivo has until now been lacking.We have used inflammatory arthritis as a model in which to test the above hypothesis. Elevated levels of proinflammatory cytokine production characterize RA synovial inflammation (11). Moreover, successful therapeutic targeting of cytokines in RA, particularly TNF-α, has demonstrated their critical pathogenetic importance. Th1 responses predominate within RA synovial T cell subsets and contribute significantly to dysregulated cytokine production (12, 13, 14). Synovial Th1 cells may drive macrophage cytokine release through secretion of IFN-γ or IL-17 (15), or may act through direct cognate cell-cell membrane interactions, involving several ligand pairs including LFA-1/ICAM-1 (16, 17). In this study, we document for the first time a novel anti-arthritic effect of statins. We show that simvastatin can effectively suppress murine collagen-induced arthritis (CIA), either prophylactically, or if administered after clinically evident onset of disease, via specific suppression of the pathologic Th1 and proinflammatory responses. The clinical relevance of these observations is illustrated by parallel studies in RA-derived human cells in which simvastatin suppressed cytokine release by PBMCs and by macrophages following cell contact-dependent interaction with activated T lymphocytes.
Original languageEnglish
Pages (from-to)1524-30
Number of pages7
JournalThe Journal of Immunology
Volume170
Issue number3
DOIs
Publication statusPublished - 1 Feb 2003
Externally publishedYes

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Simvastatin
Arthritis
Anti-Inflammatory Agents
Cytokines
Rheumatoid Arthritis
T-Lymphocytes
Macrophages
Hydroxymethylglutaryl CoA Reductases
Lymphocyte Function-Associated Antigen-1
Experimental Arthritis
Intercellular Adhesion Molecule-1
Coenzyme A
Cholesterol
Inflammation
Prenylation
Lovastatin
Interleukin-15
Mevalonic Acid
Th1 Cells

Keywords

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antigens, CD28
  • Antigens, CD3
  • Arthritis, Experimental
  • Arthritis, Rheumatoid
  • Cells, Cultured
  • Coculture Techniques
  • Collagen
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte
  • Humans
  • Immune Sera
  • Immunosuppressive Agents
  • Injections, Intraperitoneal
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred CBA
  • Simvastatin
  • Th1 Cells

Cite this

Leung, B. P., Sattar, N., Crilly, A., Prach, M., McCarey, D. W., Payne, H., ... McInnes, I. B. (2003). A novel anti-inflammatory role for simvastatin in inflammatory arthritis. The Journal of Immunology, 170(3), 1524-30. https://doi.org/10.4049/jimmunol.170.3.1524
Leung, Bernard P. ; Sattar, Naveed ; Crilly, Anne ; Prach, Morag ; McCarey, David W. ; Payne, Helen ; Madhok, Rajan ; Campbell, Carol ; Gracie, J. Alastair ; Liew, Foo Y. ; McInnes, Iain B. / A novel anti-inflammatory role for simvastatin in inflammatory arthritis. In: The Journal of Immunology. 2003 ; Vol. 170, No. 3. pp. 1524-30.
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Leung, BP, Sattar, N, Crilly, A, Prach, M, McCarey, DW, Payne, H, Madhok, R, Campbell, C, Gracie, JA, Liew, FY & McInnes, IB 2003, 'A novel anti-inflammatory role for simvastatin in inflammatory arthritis' The Journal of Immunology, vol. 170, no. 3, pp. 1524-30. https://doi.org/10.4049/jimmunol.170.3.1524

A novel anti-inflammatory role for simvastatin in inflammatory arthritis. / Leung, Bernard P.; Sattar, Naveed; Crilly, Anne; Prach, Morag; McCarey, David W.; Payne, Helen; Madhok, Rajan; Campbell, Carol; Gracie, J. Alastair; Liew, Foo Y.; McInnes, Iain B.

In: The Journal of Immunology, Vol. 170, No. 3, 01.02.2003, p. 1524-30.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel anti-inflammatory role for simvastatin in inflammatory arthritis

AU - Leung, Bernard P.

AU - Sattar, Naveed

AU - Crilly, Anne

AU - Prach, Morag

AU - McCarey, David W.

AU - Payne, Helen

AU - Madhok, Rajan

AU - Campbell, Carol

AU - Gracie, J. Alastair

AU - Liew, Foo Y.

AU - McInnes, Iain B.

PY - 2003/2/1

Y1 - 2003/2/1

N2 - 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-γ release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)3 reductase inhibitors (statins) have been unequivocally shown to reduce cardiovascular morbidity and mortality (1, 2). Although such clinical benefits are mediated in part through lipid modulation, recent studies demonstrate broader properties for statins, particularly in modifying inflammatory pathways ongoing within the atherosclerotic lesion (3). The molecular mechanisms subserving such immunomodulatory activities remain unclear. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid (MVA) during cholesterol synthesis. Downstream metabolites, including geranylgeranyl pyrophosphate and farnesyl pyrophosphate regulate prenylation within several critical signaling pathways (4). Statins inhibit IFN-γ-inducible macrophage MHC class II expression via class II transactivator suppression (5) and activate peroxisome proliferator-activated receptor-α via inhibition of Rho-dependent pathways (6). Moreover, some statins (e.g., lovastatin, simvastatin) may modulate T cell costimulation through direct effects on LFA-1/ICAM-1 interactions, dependent upon recognition of a novel statin binding site on β2integrins (7). These properties indicate that statins might modulate functional maturation of T lymphocytes.Following Ag exposure, T lymphocytes mature to different functional phenotypes distinguished on the pattern of cytokine production. Th1 responses, characterized by IFN-γ release, are critical to the development and course of several important autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (8), and have a postulated role in vascular wall inflammation (9, 10). However, definitive proof that statins can modify Th1/Th2 responses with immunopathologic consequence in vivo has until now been lacking.We have used inflammatory arthritis as a model in which to test the above hypothesis. Elevated levels of proinflammatory cytokine production characterize RA synovial inflammation (11). Moreover, successful therapeutic targeting of cytokines in RA, particularly TNF-α, has demonstrated their critical pathogenetic importance. Th1 responses predominate within RA synovial T cell subsets and contribute significantly to dysregulated cytokine production (12, 13, 14). Synovial Th1 cells may drive macrophage cytokine release through secretion of IFN-γ or IL-17 (15), or may act through direct cognate cell-cell membrane interactions, involving several ligand pairs including LFA-1/ICAM-1 (16, 17). In this study, we document for the first time a novel anti-arthritic effect of statins. We show that simvastatin can effectively suppress murine collagen-induced arthritis (CIA), either prophylactically, or if administered after clinically evident onset of disease, via specific suppression of the pathologic Th1 and proinflammatory responses. The clinical relevance of these observations is illustrated by parallel studies in RA-derived human cells in which simvastatin suppressed cytokine release by PBMCs and by macrophages following cell contact-dependent interaction with activated T lymphocytes.

AB - 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-γ release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)3 reductase inhibitors (statins) have been unequivocally shown to reduce cardiovascular morbidity and mortality (1, 2). Although such clinical benefits are mediated in part through lipid modulation, recent studies demonstrate broader properties for statins, particularly in modifying inflammatory pathways ongoing within the atherosclerotic lesion (3). The molecular mechanisms subserving such immunomodulatory activities remain unclear. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid (MVA) during cholesterol synthesis. Downstream metabolites, including geranylgeranyl pyrophosphate and farnesyl pyrophosphate regulate prenylation within several critical signaling pathways (4). Statins inhibit IFN-γ-inducible macrophage MHC class II expression via class II transactivator suppression (5) and activate peroxisome proliferator-activated receptor-α via inhibition of Rho-dependent pathways (6). Moreover, some statins (e.g., lovastatin, simvastatin) may modulate T cell costimulation through direct effects on LFA-1/ICAM-1 interactions, dependent upon recognition of a novel statin binding site on β2integrins (7). These properties indicate that statins might modulate functional maturation of T lymphocytes.Following Ag exposure, T lymphocytes mature to different functional phenotypes distinguished on the pattern of cytokine production. Th1 responses, characterized by IFN-γ release, are critical to the development and course of several important autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (8), and have a postulated role in vascular wall inflammation (9, 10). However, definitive proof that statins can modify Th1/Th2 responses with immunopathologic consequence in vivo has until now been lacking.We have used inflammatory arthritis as a model in which to test the above hypothesis. Elevated levels of proinflammatory cytokine production characterize RA synovial inflammation (11). Moreover, successful therapeutic targeting of cytokines in RA, particularly TNF-α, has demonstrated their critical pathogenetic importance. Th1 responses predominate within RA synovial T cell subsets and contribute significantly to dysregulated cytokine production (12, 13, 14). Synovial Th1 cells may drive macrophage cytokine release through secretion of IFN-γ or IL-17 (15), or may act through direct cognate cell-cell membrane interactions, involving several ligand pairs including LFA-1/ICAM-1 (16, 17). In this study, we document for the first time a novel anti-arthritic effect of statins. We show that simvastatin can effectively suppress murine collagen-induced arthritis (CIA), either prophylactically, or if administered after clinically evident onset of disease, via specific suppression of the pathologic Th1 and proinflammatory responses. The clinical relevance of these observations is illustrated by parallel studies in RA-derived human cells in which simvastatin suppressed cytokine release by PBMCs and by macrophages following cell contact-dependent interaction with activated T lymphocytes.

KW - Animals

KW - Anti-Inflammatory Agents, Non-Steroidal

KW - Antigens, CD28

KW - Antigens, CD3

KW - Arthritis, Experimental

KW - Arthritis, Rheumatoid

KW - Cells, Cultured

KW - Coculture Techniques

KW - Collagen

KW - Disease Models, Animal

KW - Epitopes, T-Lymphocyte

KW - Humans

KW - Immune Sera

KW - Immunosuppressive Agents

KW - Injections, Intraperitoneal

KW - Macrophages

KW - Male

KW - Mice

KW - Mice, Inbred CBA

KW - Simvastatin

KW - Th1 Cells

U2 - 10.4049/jimmunol.170.3.1524

DO - 10.4049/jimmunol.170.3.1524

M3 - Article

VL - 170

SP - 1524

EP - 1530

JO - The Journal of Immunology

JF - The Journal of Immunology

SN - 0022-1767

IS - 3

ER -