A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis

Morten Aagaard Nielsen; Thomas Andersen; Anders Etzerodt; Tue Wenzel Kragstrup; Tue Kruse Rasmussen; Kristian Stengaard-Pedersen; Merete Lund Hetland; Kim Hørslev-Petersen; Peter Junker; Mikkel Østergaard; Malene Hvid; Søren K Moestrup; Bent Deleuran

doi:10.1093/rheumatology/kew237

A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis

Morten Aagaard Nielsen, Thomas Andersen, Anders Etzerodt, Tue Wenzel Kragstrup, Tue Kruse Rasmussen, Kristian Stengaard-Pedersen, Merete Lund Hetland, Kim Hørslev-Petersen, Peter Junker, Mikkel Østergaard, Malene Hvid, Søren K Moestrup, Bent Deleuran

Department of Clinical Medicine

5 Citations (Scopus)

Abstract

OBJECTIVE: Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA.

METHODS: Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-naïve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period.

RESULTS: RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing.

CONCLUSION: ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.

Original language	English
Journal	Rheumatology (Oxford, England)
Volume	55
Issue number	10
Pages (from-to)	1871-1879
Number of pages	9
ISSN	1462-0324
DOIs	https://doi.org/10.1093/rheumatology/kew237
Publication status	Published - 1 Oct 2016

Keywords

4-1BB Ligand
ADAM17 Protein
Antirheumatic Agents
Arthritis, Rheumatoid
Autoantibodies
CD8-Positive T-Lymphocytes
Cells, Cultured
Disease Progression
Double-Blind Method
Enzyme-Linked Immunosorbent Assay
Galectins
HEK293 Cells
Humans
Leukocytes, Mononuclear
Longitudinal Studies
Matrix Metalloproteinase 17
Methotrexate
Synovial Fluid
T-Lymphocytes
Tumor Necrosis Factor-alpha
Journal Article
Multicenter Study
Randomized Controlled Trial

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Nielsen, M. A., Andersen, T., Etzerodt, A., Kragstrup, T. W., Rasmussen, T. K., Stengaard-Pedersen, K., Hetland, M. L., Hørslev-Petersen, K., Junker, P., Østergaard, M., Hvid, M., Moestrup, S. K., & Deleuran, B. (2016). A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis. Rheumatology (Oxford, England), 55(10), 1871-1879. https://doi.org/10.1093/rheumatology/kew237

A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis. / Nielsen, Morten Aagaard; Andersen, Thomas; Etzerodt, Anders et al.

In: Rheumatology (Oxford, England), Vol. 55, No. 10, 01.10.2016, p. 1871-1879.

Research output: Contribution to journal › Journal article › Research › peer-review

Nielsen, MA, Andersen, T, Etzerodt, A, Kragstrup, TW, Rasmussen, TK, Stengaard-Pedersen, K, Hetland, ML, Hørslev-Petersen, K, Junker, P, Østergaard, M, Hvid, M, Moestrup, SK & Deleuran, B 2016, 'A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis', Rheumatology (Oxford, England), vol. 55, no. 10, pp. 1871-1879. https://doi.org/10.1093/rheumatology/kew237

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title = "A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis",

abstract = "OBJECTIVE: Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA.METHODS: Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-na{\"i}ve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period.RESULTS: RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing.CONCLUSION: ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.",

keywords = "4-1BB Ligand, ADAM17 Protein, Antirheumatic Agents, Arthritis, Rheumatoid, Autoantibodies, CD8-Positive T-Lymphocytes, Cells, Cultured, Disease Progression, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Galectins, HEK293 Cells, Humans, Leukocytes, Mononuclear, Longitudinal Studies, Matrix Metalloproteinase 17, Methotrexate, Synovial Fluid, T-Lymphocytes, Tumor Necrosis Factor-alpha, Journal Article, Multicenter Study, Randomized Controlled Trial",

author = "Nielsen, {Morten Aagaard} and Thomas Andersen and Anders Etzerodt and Kragstrup, {Tue Wenzel} and Rasmussen, {Tue Kruse} and Kristian Stengaard-Pedersen and Hetland, {Merete Lund} and Kim H{\o}rslev-Petersen and Peter Junker and Mikkel {\O}stergaard and Malene Hvid and Moestrup, {S{\o}ren K} and Bent Deleuran",

note = "{\textcopyright} The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected].",

year = "2016",

month = oct,

day = "1",

doi = "10.1093/rheumatology/kew237",

language = "English",

volume = "55",

pages = "1871--1879",

journal = "Rheumatology",

issn = "1462-0324",

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TY - JOUR

T1 - A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis

AU - Nielsen, Morten Aagaard

AU - Andersen, Thomas

AU - Etzerodt, Anders

AU - Kragstrup, Tue Wenzel

AU - Rasmussen, Tue Kruse

AU - Stengaard-Pedersen, Kristian

AU - Hetland, Merete Lund

AU - Hørslev-Petersen, Kim

AU - Junker, Peter

AU - Østergaard, Mikkel

AU - Hvid, Malene

AU - Moestrup, Søren K

AU - Deleuran, Bent

PY - 2016/10/1

Y1 - 2016/10/1

N2 - OBJECTIVE: Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA.METHODS: Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-naïve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period.RESULTS: RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing.CONCLUSION: ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.

AB - OBJECTIVE: Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA.METHODS: Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-naïve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period.RESULTS: RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing.CONCLUSION: ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.

KW - 4-1BB Ligand

KW - ADAM17 Protein

KW - Antirheumatic Agents

KW - Arthritis, Rheumatoid

KW - Autoantibodies

KW - CD8-Positive T-Lymphocytes

KW - Cells, Cultured

KW - Disease Progression

KW - Double-Blind Method

KW - Enzyme-Linked Immunosorbent Assay

KW - Galectins

KW - HEK293 Cells

KW - Humans

KW - Leukocytes, Mononuclear

KW - Longitudinal Studies

KW - Matrix Metalloproteinase 17

KW - Methotrexate

KW - Synovial Fluid

KW - T-Lymphocytes

KW - Tumor Necrosis Factor-alpha

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

U2 - 10.1093/rheumatology/kew237

DO - 10.1093/rheumatology/kew237

M3 - Journal article

C2 - 27330157

SN - 1462-0324

VL - 55

SP - 1871

EP - 1879

JO - Rheumatology

JF - Rheumatology

IS - 10

ER -

A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis

Abstract

Keywords

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