Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

Abstract

Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

“…Moreover, IL-23 is an essential factor in the survival and expansion of Th17 cells [5], which produce cytokines including IL-17, IL-17F, IL-22, IL-6 and TNF-a [6]. p19-deficient mice are highly resistant to the development of experimental allergic encephalomyelitis (EAE) [7], and it has been shown that the IL-23-dependent production of IL-17, but not IL-22 [8], is important for the pathogenesis of autoimmune diseases such as EAE [9]. Recent studies have also revealed that the IL-23-dependent production of IL-22, but not IL-17, plays a critical role in protection against subsequent infection.…”

“…Moreover, IL-23 is an essential factor in the survival and expansion of Th17 cells [5], which produce cytokines including IL-17, IL-17F, . p19-deficient mice are highly resistant to the development of experimental allergic encephalomyelitis (EAE) [7], and it has been shown that the IL-23-dependent production of IL-17, but not , is important for the pathogenesis of autoimmune …”

“…Therefore, whether or not IL-23 plays any role in the regulation of hepatitis remains unknown. In the present study, we investigated the role of IL-23 in the induction of IL-22 and IL-17 production and liver damage during Con A-induced hepatitis using IL-23p19-and IL-17-deficient mice [7]. We found that endogenous IL-23 plays a protective role in hepatitis in an IL-22-dependent manner, whereas exogenous IL-23 plays a pathological role in IL-17-dependent and -independent manners.…”

Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

“…Upon maturation, they then secrete cytokines such as IL-12 and IL-23 that regulate inflammation. In particular, IL-23 is a potent inflammatory cytokine which plays a crucial role in the inflammation of the brain (Cua et al, 2003). The expression of the specific IL-23p19 subunit in transgenic mice also results in systemic inflammation (Wiekowski et al, 2001).…”

Single‐cell technologies to study the immune system

“…In 1995 Dr Sakaguchi60, 61 discovered another specific subpopulation of T cells, named regulatory T (Treg) cells, that were specialized for immunosuppression. More recently other subsets have been isolated named Th17 (2005),62, 63 Th9 (2008)64, 65 and Th22 (2009) 40. Finally, single‐cell RNA ‐sequencing has revealed the existence of a subpopulation of steroid‐producing cells within the Th2 compartment 23…”