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JAK/STAT/PKCδ molecular pathways in synovial fluid T lymphocytes reflect the in vivo T helper-17 expansion in psoriatic arthritis

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Abstract

Looking to the sustained psoriatic arthritis (PsA) joint as a model of local human inflammation, this study was designed to assess the T lymphocyte signal transduction pathways potentially involved in this chronic immune-mediated inflammatory process, as characterized by direct ex vivo analysis of T helper (Th)-17 T effector (Teff) cell phenotypes in synovial fluid (SF) and peripheral blood (PB) of clinically active PsA patients. The reverse-phase protein arrays (RPPA) technique was employed to identify STAT3, STAT1, JAK1, JAK2, PKCδ and ERK1/2 phosphoprotein levels on total T cell lysates in SF samples of PsA patients. Frequencies of T CD4+IL-17A-F+ and T CD4+IL-23R+ Th17 cells were quantified in SF and matched PB of PsA patients by flow cytometry and compared with PB of healthy controls (HC). Increased levels of JAK1, STAT3, STAT1 and PKCδ phosphoproteins were found in SF T cells of PsA patients, compared with PB of HC. The expansion of T CD4+IL-17A-F+ cells, as well as of T CD4+ cells expressing IL-23Rp19 (T CD4+ IL-23R+), considered as the pathogenic phenotype of effector Th17 cells, was found to be confined to the joints of PsA patients, as the frequencies of both populations were significantly higher in SF than in matched PB, or in PB of HC. In conclusion, T lymphocyte signal transduction pathway mapping revealed an enhanced activation of JAK1/STAT3/STAT1 and PKCδ phosphoproteins that may drive the local inflammatory process, characterized by the in vivo expansion of T CD4+IL-17A-F+ and T CD4+IL-23R+ Th17 Teff cells in SF of clinically active joints of PsA patients.

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Abbreviations

AS:

Ankylosing spondylitis

CASPAR:

Classification criteria for psoriatic arthritis

CD:

Cluster of differentiation

CK:

Cytokine

CRP:

C-reactive protein

CCR:

Chemokine receptor

ESR:

Erythrocyte sedimentation rate

ERK:

Extracellular signal-regulated kinase

FACS:

Fluorescence-activated cell sorter

FOXP:

Intracellular fork head box transcription factor

HC:

Healthy controls

IgG:

Immunoglobulins G

IL:

Interleukin

INF-γ:

Interferon gamma

JAK:

Janus-associated kinase

MAb:

Monoclonal antibody

MAPK:

Mitogen-activated protein kinase

MC:

Mononuclear cells

MFI:

Mean log fluorescence intensity

NF-κB:

Nuclear factor-κB

NK:

Natural killer

PASI:

Psoriasis area and severity index

PB:

Peripheral blood

PKC:

Protein kinase C

PS:

Psoriasis

PsA:

Psoriatic arthritis

R:

Receptor

RA:

Rheumatoid arthritis

RORC:

Receptor-related orphan receptor C

RPPA:

Reverse-phase protein arrays

SF:

Synovial fluid

STAT:

Signal transducer and activator of transcription

Teff:

Effector T cells

TGF-β:

Transforming growth factor beta

Th:

T helper cells

TNF-α:

Tumor necrosis factor alpha

Treg:

Regulatory T cells

Tyr:

Tyrosine

WBC:

White blood cell

WB:

Western blot

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Acknowledgments

This work was supported by Grants from the Italian Ministry of Education, University and Research (MIUR-2009EE3SWA; FIRB 2011); the Istituto Superiore di Sanita` (Italy/USA program); and the Fondazione Città della Speranza.

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The authors declare that they have no conflict of interest.

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Fiocco, U., Accordi, B., Martini, V. et al. JAK/STAT/PKCδ molecular pathways in synovial fluid T lymphocytes reflect the in vivo T helper-17 expansion in psoriatic arthritis. Immunol Res 58, 61–69 (2014). https://doi.org/10.1007/s12026-013-8481-0

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