The unfolded protein response (UPR) is a conserved mechanism by which cells cope with endogenous threats result in endoplasmic reticulum (ER) stress. Our laboratory has shown that HLA-B27, a human MHC-encoded class I molecule, has a tendency to misfold and accumulate in the ER resulting in UPR activation. HLA-B27 is highly associated with ankylosing spondylitis (AS) and other spondyloarthropathies. Despite long-standing recognition of a striking relationship between HLA-B27 and spondyloarthritis, the mechanism of disease remains unclear.
Results from our laboratory have revealed that IL-17 production is increased in HLA-B27 transgenic rats that serve as a spondyloarthritis model. In these rats it is known that CD4+ T cells are critical for pathogenesis while CD8 T cells are dispensable, and that IL-17-producing T cells are increased in the colon tissue. Based on these results, and evidence that IL-17 production can be driven by IL-23, we focused on the question of whether macrophages exhibiting UPR activation produce elevated levels of IL-23.
Here, we show that IL-23p19 mRNA is highly upregulated (90-fold) in macrophages experiencing ER stress when further stimulated with LPS. This response is robust and seen at several concentrations of LPS. Furthermore IL-12p35 mRNA is increased 4-fold and IL-12/23p40 mRNA is decreased 3-fold over LPS alone. These mRNA inductions correspond to a 23-fold increase in production of immunoreactive IL-23, while IL-12 is increased 3-fold.
Our results suggest that ER stress may enhance production of cytokines that can drive the activation of critical T cell populations. Moreover, there may be a greater polarization toward Th17 IL-23 production, suggesting that Th17 T cells might be preferentially activated. These data raise the possibility that at least one role of HLA-B27 in disease might be to activate ER stress pathways secondary to misfolding, and promote IL-23 production which in turn may activate the IL-23/17 axis and promote inflammation in AS and related disorders.