Vol.23 No.6

Original Article

The roles of IFN-γ versus IL-17 in pathogenic effects of human Th17 cells on synovial fibroblasts

Authors

Hiroshi Kato1 , Judith Endres 1 , David A. Fox2

  • University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI, USA
  • University of Michigan Medical Center, Suite 7C27, 300 North Ingalls Street, SPC 5422, Ann Arbor, MI 48109-5422, USA
Received:

28 August 2012

Accepted:

4 December 2012

Published online:

11 January 2013

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Abstract

Objectives Th17 cells, while indispensable in host defense, may play pathogenic roles in many autoimmune diseases, including rheumatoid arthritis (RA). However, the mechanisms by which human Th17 cells drive autoimmunity have not been fully defined. We assessed the potential of the human Th17 CD4 T cell subset to induce expression of cell?cell interaction molecules and inflammatory mediators by fibroblast-like synoviocytes (FLS), and the roles of IFN-c and IL-17 in these interactions.
Methods Th1 or Th17 cells were induced from healthy adult donor CD4 T cells and were co-cultured with FLS for 48 h with/without neutralization of IFN-c, IL-17A, or both.
Alternatively, FLS were treated only with IFN-c or IL-17 for 48 h. FLS expression of CD40, CD54, and MHC-II, as well as IL-6 and IL-8 secretion, were assessed by surface staining followed by flow cytometry and ELISA, respectively.
Results Both Th1 and Th17 cells secreted IL-17 as well as IFN-c, although IFN-c production was much greater from Th1 cells. FLS expression of CD40, CD54, and MHC-II significantly increased upon co-culture with Th1 cells, while Th17 cells increased only the percentage of FLS that were CD54?. Both T cell subsets induced IL-6 and IL-8 secretion by RA FLS. Neutralization of IL-17A did not reduce FLS expression of CD40, MHC-II, or CD54, but did inhibit IL-6 and IL-8 secretion. Although IFN-c was a weak inducer of IL-6 secretion and significantly inhibited IL-8 secretion from FLS when used as a single stimulus, neutralization of IFN-c inhibited the secretion of both cytokines in Th17/FLS co-cultures with RA but not OA FLS.
Conclusion FLS cell?cell interaction molecules and soluble inflammatory mediators are differentially regulated by IFN-c and IL-17. The effects of IFN-c may depend in part on the particular milieu of other co-existing cytokines and its potential to induce cell?cell interactions. The potential benefit of therapeutic neutralization of either IL-17 or IFNc could depend on the relative proportions of these cytokines in the synovial compartment of an RA patient.

Key words

Fibroblast-like synoviocytes, Rheumatoid arthritis, Osteoarthritis, T lymphocyte subsets, Cytokines