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

ABSTRACT: 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-? and IL-17 in these interactions.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-?, IL-17A, or both. Alternatively, FLS were treated only with IFN-? 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.Both Th1 and Th17 cells secreted IL-17 as well as IFN-?, although IFN-? 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-? 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-? inhibited the secretion of both cytokines in Th17/FLS co-cultures with RA but not OA FLS.FLS cell-cell interaction molecules and soluble inflammatory mediators are differentially regulated by IFN-? and IL-17. The effects of IFN-? 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 IFN-? could depend on the relative proportions of these cytokines in the synovial compartment of an RA patient.

SUBMITTER: Kato H

PROVIDER: S-EPMC3710715 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

Kato Hiroshi H Endres Judith J Fox David A DA

Modern rheumatology 20130111 6

<h4>Objectives</h4>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-γ and IL-17 in these interactions.<h4 ...[more]

PMID: 23306426

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Project description:In Plasmodium falciparum holoendemic transmission regions of western Kenya, life-threatening pediatric malaria manifests primarily as severe malarial anemia (SMA, Hb≤6.0 g/dL with any density parasitemia). To determine the role that CD4+ T-cell-driven inflammatory responses have in the pathogenesis of SMA, peripheral CD4+ T-cell populations and their intracellular production of pro-inflammatory cytokines (IFN-γ and IL-17) were characterized in children aged 12-36 months of age stratified into two groups: non-severe malarial anemia (non-SMA, Hb≥6.0 g/dL, n = 50) and SMA (n = 39). In addition, circulating IFN-γ and IL-17 were measured as part of a Cytokine 25-plex Antibody Bead Kit, Human (BioSource™ International). Children with SMA had higher overall proportions of circulating lymphocytes (P = 0.003) and elevated proportions of lymphocytes expressing IFN-γ (P = 0.014) and comparable IL-17 (P = 0.101). In addition, SMA was characterized by decreased memory-like T-cells (CD4+CD45RA-) expressing IL-17 (P = 0.009) and lower mean fluorescence intensity in memory-like CD4+ T-cells for both IFN-γ (P = 0.063) and IL-17 (P = 0.006). Circulating concentrations of IFN-γ were higher in children with SMA (P = 0.009), while IL-17 levels were comparable between the groups (P = 0.164). Furthermore, circulating levels of IFN-γ were negatively correlated with IL-17 levels in both groups of children (SMA: r = -0.610, P = 0.007; and non-SMA: r = -0.516, P = 0.001), while production of both cytokines by lymphocytes were positively correlated (SMA: r = 0.349, P = 0.037; and non-SMA: r = 0.475, P = 0.001). In addition, this correlation was only maintained by the memory-like CD4+ T cells (r = 0.365, P = 0.002) but not the naïve-like CD4+ T cells. However, circulating levels of IFN-γ were only associated with naïve-like CD4+ T cells producing IFN-γ (r = 0.547, P = 0.028), while circulating levels of IL-17 were not associated with any of the cell populations. Taken together, these results suggest that enhanced severity of malarial anemia is associated with higher overall levels of circulating lymphocytes, enhanced intracellular production of IFN-γ by peripheral lymphocytes and high circulating IFN-γ levels. In addition, the observed inverse relationship between the circulating levels of IFN-γ and IL-17 together with the reduction in the levels of memory-like CD4+ T cells expressing IL-17 in children with SMA may suggest possible relocation of these cells in the deeper tissues for their pathological effect.

Dataset Information

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

Publications

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

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