Regulation of IL-17A Production Is Distinct from IL-17F in a Primary Human Cell Co-culture Model of T Cell-Mediated B Cell Activation

Abstract

Improper regulation of B cell responses leads to excessive production of antibodies and contributes to the development of autoimmune disease. T helper 17 (Th17) cells also drive the development of autoimmune disease, but the role of B cells in shaping Th17 cell-mediated immune responses, as well as the reciprocal regulation of B cell responses by IL-17 family cytokines, remains unclear. The aim of this study was to characterize the regulation of IL-17A and IL-17F in a model of T cell-dependent B cell activation. Stimulation of primary human B cell and peripheral blood mononuclear cell (BT) co-cultures with α-IgM and a non-mitogenic concentration of superantigens for three days promoted a Th17 cell response as evidenced by increased expression of Th17-related gene transcripts, including Il17f, Il21, Il22, and Il23r, in CD4 T cells, as well as the secretion of IL-17A and IL-17F protein. We tested the ability of 144 pharmacologic modulators representing 91 different targets or pathways to regulate IL-17A and IL-17F production in these stimulated BT co-cultures. IL-17A production was found to be preferentially sensitive to inhibition of the PI3K/mTOR pathway, while prostaglandin EP receptor agonists, including PGE2, increased IL-17A concentrations. In contrast, the production of IL-17F was inhibited by PGE2, but selectively increased by TLR2 and TLR5 agonists. These results indicate that IL-17A regulation is distinct from IL-17F in stimulated BT co-cultures and that this co-culture approach can be used to identify pathway mechanisms and novel agents that selectively inhibit production of IL-17A or IL-17F.

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases

“…Comparing the effects of our compounds with a proprietary database of >3000 approved drugs and experimental agents failed to find any close matches (Berg et al, 2010). The levels of interleukin 17A and 17F usually rise and fall together (Melton et al, 2013), but treatment with our compounds elicited an unusual split response, with an increase in IL-17A and a corresponding decrease in IL-17F (BT condition: Figure 6C, Figure 6—figure supplement 1 and Figure 6—source data 1). Overall, the pattern observed across the biomarkers was consistent with the effects of our compounds on inflammation (VCAM-1, sPGE2 and IL-8), immunomodulation (IL-17A, IL-17F, HLA-DR and IgG) and tissue remodelling (uPAR) (Figure 6C and Figure 6—source data 1).…”

Complex Primary Human Cell Systems for Drug Discovery

“…Tofacitinib is highly active in the BioMAP BT system, a model of T cell-dependent B cell activation. 26 Tofacitinib reduces the levels of IgG, IL-6 and TNFa as well as IL-17A in this system, and also causes an increase in IL-2 levels. Inhibition of IgG, IL-6 and TNFa are consistent with efficacy in RA, as these are all clinical biomarkers for the disease.…”

“…Immunomodulatory activities include strong inhibition of activities in the BT system, a model of T celldependent B cell activation. 26 Activities consistent with tissue remodelling biology include inhibition of MMP3, uPA and uPAR.…”

Vitamin D, Inflammation, and Colorectal Cancer Progression: A Review of Mechanistic Studies and Future Directions for Epidemiological Studies

“…It inhibits IL17A and IL17F production in immune cells (53). Moreover, it was shown in patients with Behcet's disease and asthma that calcitriol reduced IL17 levels (54,55).…”