Nature Reviews Immunology 3, 262 (2003)
CYTOKINES
Common-chain confusion
Elaine Bell
The heterodimeric cytokine interleukin-12 (IL-12) — which is composed of p35 and p40 subunits — is important for the differentiation of naive T cells to T helper 1 (TH1) cells and for T-cell responses in vivo. But, many of the studies investigating the function of IL-12 have used IL-12 p40-deficient mice or antibodies specific for the p40 subunit, which is also a component of the recently characterized cytokine IL-23. Now, Daniel Cua and colleagues have generated mice deficient for IL-23 alone, and they show that IL-23, not IL-12, is the crucial cytokine controlling autoimmune inflammation in the brain.
IL-23-deficient mice were generated by targeting the p19 subunit of IL-23. The role of IL-23 was assessed using a MOG (myelin oligodendrocyte 35–55)-induced model of experimental autoimmune encephalomyelitis (EAE), in which inflammation of the central nervous system (CNS) is mediated by TH1 cells and inflammatory macrophages. p35-deficient mice (lacking IL-12 only) were susceptible to EAE, whereas p40-deficient mice (lacking IL-12 and IL-23) and p19-deficient mice (lacking IL-23 only) were resistant to EAE. Introduction of IL-23 into the CNS of mice lacking IL-23 using gene-transfer vectors reconstituted susceptibility to EAE, although the mice lacking both IL-12 and IL-23 had delayed onset and severity of disease. Supplying p40-deficient mice with either IL-12 (from day 0), or IL-12 (from day 0) plus IL-23 (from day 8), during the induction of EAE showed that IL-12 alone did not lead to EAE but that the combined cytokine treatment did, which indicates that IL-23 is important for inflammatory events that follow the induction of TH1 cells.
The authors then took a closer look at T-cell responses compared with macrophage responses. Mice lacking IL-23 alone generated MOG-specific T-cell responses, but IL-12-deficient mice could only develop TH2-cell responses. MOG-specific T cells and inflammatory macrophages (CD4-CD11b+CD45hi) could migrate to the CNS in IL-12-deficient mice, but this did not lead to the further recruitment of T cells or macrophages, and the resident macrophages (or microglia) were not activated.
Using real-time quantitative PCR to assess the expression of cytokine and cytokine-receptor genes, the authors observed that IL-23 is produced by inflammatory macrophages and microglial cells, but that only the former cells can respond to IL-23. By contrast, IL-12 is produced mainly by inflammatory macrophages, but both cell types can respond to it.
So, previous data from studies involving p40 might need to be reinterpreted with regard to the role of IL-12. This study shows that IL-23 mediates the later inflammatory events that follow the induction of TH1 cells. As IL-23 seems to be important for chronic inflammation, it could be a good therapeutic target for many autoimmune inflammatory diseases. |
