cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing Tregs.
Sci Adv
; 5(5): eaaw5422, 2019 05.
Article
in En
| MEDLINE
| ID: mdl-31049403
ABSTRACT
IL-17 and TNF-α are major effector cytokines in chronic inflammation. TNF-α inhibitors have revolutionized the treatment of rheumatoid arthritis (RA), although not all patients respond, and most relapse after treatment withdrawal. This may be due to a paradoxical exacerbation of TH17 responses by TNF-α inhibition. We examined the therapeutic potential of targeting cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) in inflammation by its influence on human TH subsets and mice with collagen-induced arthritis. Inhibition of cIAP1/2 abrogated CD4+ IL-17A differentiation and IL-17 production. This was a direct effect on T cells, mediated by reducing NFATc1 expression. In mice, cIAP1/2 inhibition, when combined with etanercept, abrogated disease activity, which was associated with an increase in Tregs and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between TH17 and Tregs and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arthritis, Experimental
/
Arthritis, Rheumatoid
/
Autoimmunity
/
Tumor Necrosis Factor-alpha
/
T-Lymphocytes, Regulatory
/
Interleukin-17
/
Ubiquitin-Protein Ligases
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Inhibitor of Apoptosis Proteins
/
Baculoviral IAP Repeat-Containing 3 Protein
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Sci Adv
Year:
2019
Document type:
Article
Affiliation country:
United kingdom