Investigating the role of the interleukin-23/-17A axis in rheumatoid arthritis.
OBJECTIVE
IL-23 is a pro-inflammatory cytokine proposed to be central to the development of autoimmune disease. We investigated whether IL-23, together with the downstream mediator IL-17A, was present and functional in RA in humans.


METHODS
RA synovial cells were cultured in the presence or absence of antibodies directed against IL-23p19 or -23R and -17. IL-23, -12, -17, and their receptors, and IL-6, -1beta and TNF-alpha were measured by ELISA and/or PCR.


RESULTS
Small amounts of cell-associated IL-23 (median 110 pg/ml) were detected in RA synovial cultures, and found to be functional as IL-23R blockade resulting in a significant inhibition of TNF-alpha (57%), IL-1beta (51%) and IL-6 (30%). However, there was a considerable variability between individual patient samples, and anti-IL-23p19 was found to be considerably less effective. IL-17A protein was detected in approximately 40% of the supernatants and IL-17A blockade, in IL-17A-producing cultures, resulted in a small but significant inhibition of TNF-alpha (38%), IL-1beta (23%) and IL-6 (22%). Addition of recombinant IL-23 to cultures had a variable effect on the spontaneous production of endogenous IL-17A with enhancement observed in some but not all cultures, suggesting that either the low levels of endogenous IL-23 are sufficient to support cytokine production and/or that the relevant Th17 cells were not present.


CONCLUSIONS
These results suggest that although IL-23 may have pathogenic activity in a proportion of patients with late-stage RA, it is not abundantly produced in this inflammatory tissue, nor does it have a dominant role in all patient tissues analysed.
Hillyer
Philippa
P
Kennedy Institute of Rheumatology, Imperial College London, 1 Aspenlea Road, London W6 8LH, UK.
Larché
Maggie J
MJ
Bowman
Edward P
EP
McClanahan
Terrill K
TK
de Waal Malefyt
Rene
R
Schewitz
Lauren P
LP
Giddins
Grey
G
Feldmann
Marc
M
Kastelein
Robert A
RA
Brennan
Fionula M
FM
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001681:Biological Assay / Q000379:methods; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology
C515500:IL23R protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D011994:Recombinant Proteins