IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients

M A Ortiz; C Diaz-Torné; M V Hernández; D Reina; D de la Fuente; I Castellví; P Moya; J M Ruiz; H Corominas; C Zamora; E Cantó; R Sanmartí; C Juarez; S Vidal

doi:10.1016/j.clim.2015.03.025

IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients

Clin Immunol. 2015 Jun;158(2):174-82. doi: 10.1016/j.clim.2015.03.025. Epub 2015 Apr 3.

Authors

M A Ortiz¹, C Diaz-Torné², M V Hernández³, D Reina⁴, D de la Fuente⁵, I Castellví⁶, P Moya², J M Ruiz⁵, H Corominas⁴, C Zamora¹, E Cantó¹, R Sanmartí³, C Juarez⁷, S Vidal⁸

Affiliations

¹ IIB-Institut Recerca Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
² Unit of Rheumatology, Department of Internal Medicine, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
³ Arthritis Unit, Rheumatology Department, Hospital Clinic, Barcelona, Spain.
⁴ Department of Rheumatology, Hospital Moises Broggi, Sant Joan Despí, Spain.
⁵ Department of Rheumatology, Hospital de Viladecans, Viladecans, Spain.
⁶ Department of Rheumatology, Hospital Comarcal de l'Alt Penedes, Vilafranca del Penedes, Spain.
⁷ Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁸ IIB-Institut Recerca Hospital de la Santa Creu I Sant Pau, Barcelona, Spain. Electronic address: svidal@santpau.cat.

PMID: 25847223
DOI: 10.1016/j.clim.2015.03.025

Abstract

Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1+, pSTAT3+, and pSTAT6+ monocytes and pSTAT5+ lymphocytes than HDs. After 24weeks of treatment, percentages of IFNγ-induced pSTAT1+ and IL-10-induced pSTAT3+ monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1+ and pSTAT3+ cells correlated inversely with RA disease activity index and levels of pSTAT+ cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1+ cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3+ cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status.

Keywords: IL-6; Leukocytes; Rheumatoid arthritis; STATs; Tocilizumab.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antibodies, Monoclonal, Humanized / pharmacology
Arthritis, Rheumatoid / metabolism*
Female
Gene Expression Regulation / drug effects*
Humans
Interleukin-6 / antagonists & inhibitors*
Interleukin-6 / metabolism
Leukocytes / metabolism*
Middle Aged
Peptides, Cyclic / immunology
STAT1 Transcription Factor / genetics
STAT1 Transcription Factor / metabolism*
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
T-Lymphocytes, Regulatory / physiology

Substances

Antibodies, Monoclonal, Humanized
Interleukin-6
Peptides, Cyclic
STAT1 Transcription Factor
STAT1 protein, human
STAT3 Transcription Factor
STAT3 protein, human
cyclic citrullinated peptide
tocilizumab