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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftRheumatology
Vol/bind55
Udgave nummer10
Sider (fra-til)1871-1879
ISSN1462-0324
DOI
StatusUdgivet - 2016

Fingeraftryk

Disintegrins
Metalloproteases
Joints
4-1BB Ligand
RNA Interference

Citer dette

Nielsen, M. A., Andersen, T., Etzerodt, A., Kragstrup, T. W., Rasmussen, T. K., Stengaard-Pedersen, 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, 55(10), 1871-1879. https://doi.org/10.1093/rheumatology/kew237
Nielsen, Morten Aagaard ; Andersen, Thomas ; Etzerodt, Anders ; Kragstrup, Tue Wenzel ; Rasmussen, Tue Kruse ; Stengaard-Pedersen, Kristian ; Hetland, Merete Lund ; Hørslev-Petersen, Kim ; Junker, Peter ; Østergaard, Mikkel ; Hvid, Malene ; Moestrup, Søren K ; Deleuran, Bent. / A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis. I: Rheumatology. 2016 ; Bind 55, Nr. 10. s. 1871-1879.
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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.",
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 = "{\circledC} The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
year = "2016",
doi = "10.1093/rheumatology/kew237",
language = "English",
volume = "55",
pages = "1871--1879",
journal = "Rheumatology",
issn = "1462-0324",
publisher = "Heinemann",
number = "10",

}

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, bind 55, nr. 10, s. 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; Kragstrup, Tue Wenzel; Rasmussen, Tue Kruse; Stengaard-Pedersen, Kristian; Hetland, Merete Lund; Hørslev-Petersen, Kim; Junker, Peter; Østergaard, Mikkel; Hvid, Malene; Moestrup, Søren K; Deleuran, Bent.

I: Rheumatology, Bind 55, Nr. 10, 2016, s. 1871-1879.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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

N1 - © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2016

Y1 - 2016

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.

U2 - 10.1093/rheumatology/kew237

DO - 10.1093/rheumatology/kew237

M3 - Journal article

VL - 55

SP - 1871

EP - 1879

JO - Rheumatology

JF - Rheumatology

SN - 1462-0324

IS - 10

ER -