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.

A novel sequence discovered in a computational screen appears distantly related to the p35 subunit of IL-12. This factor, which we term p19, shows no biological activity by itself; instead, it combines with the p40 subunit of IL-12 to form a novel, biologically active, composite cytokine, which we term IL-23. Activated dendritic cells secrete detectable levels of this complex. IL-23 binds to IL-12R beta 1 but fails to engage IL-12R beta 2; nonetheless, IL-23 activates Stat4 in PHA blast T cells. IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population. Similar to IL-12, human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.

Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (T H 2)-type allergic inflammation is not known.We show here that human thymic stromal lymphopoietin (TSLP) potently activated CD11c + dendritic cells (DCs) and induced production of the T H 2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22).TSLP-activated DCs primed naïve T H cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-α, while downregulating IL-10 and interferon-γ. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis.TSLP expression was associated with Langerhans cell migration and activation in situ.These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLPAbout 20% of the population in Western countries suffers from allergic diseases, which include asthma, allergic rhinitis, atopic dermatitis and food allergy 1 . Allergic inflammation is the result of a complex immunological cascade that leads to dysregulated production of T helper type 2 (TH2)-derived cytokines such as interleukin 4 (IL-4), IL-5 and IL-13 2-4 , which trigger immunoglobulin E (IgE) production, eosinophilia and mucus production [5][6][7] . Dendritic cells (DCs), which are professional antigen-presenting cells 8 , play an important role in the pathogenesis of allergic diseases 9-11 . However, the initial signal that primes DCs to induce T cells to produce proallergic TH2 cytokines is unknown. Epithelial cells are located at the sites of allergen entry into the body and interact closely with DCs in situ. However, it is not known whether DCs play a role in triggering the allergic immune cascade. Although skin keratinocytes and mucosal epithelial cells produce proinflammatory cytokines such as IL-1, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) after activation 12 , none of these cytokines explain the mechanism that underlies the induction of allergic inflammation. Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, cloned from a murine thymic stromal cell line 13 . The TLSP receptor is a heterodimer that consists of the IL-7 receptor α chain (IL-7Rα) and a common γ-like receptor chain called TSLP receptor (TSLPR) [14][15][16][17] . Mouse TSLP supports murine early B and T cell developments 18,19 and does not appear to have any biological effects on murine DCs (unpublished data). In contrast, human TSLP activates CD11c + DCs, but does not appear to have any direct biological effects on B cells, T cells, NK cells, neutrophils or mast cells 17 . This is in accordance with the coexpression of IL-7Rα chain and TSLPR mRNA in CD11c + DCs, but not in other cell types. We show here that human TSLP potently activated ...

An efficient Th1-driven adaptive immune response requires activation of the T cell receptor and secretion of the T cell stimulatory cytokine IL-12 by activated antigen-presenting cells. IL-12 triggers Th1 polarization of naive CD4(+) T cells and secretion of IFN-gamma. We describe a new heterodimeric cytokine termed IL-27 that consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. IL-27 is an early product of activated antigen-presenting cells and drives rapid clonal expansion of naive but not memory CD4(+) T cells. It also strongly synergizes with IL-12 to trigger IFN-gamma production of naive CD4(+) T cells. IL-27 mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR.

IL-23 is a heterodimeric cytokine composed of the IL-12p40 “soluble receptor” subunit and a novel cytokine-like subunit related to IL-12p35, termed p19. Human and mouse IL-23 exhibit some activities similar to IL-12, but differ in their capacities to stimulate particular populations of memory T cells. Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rβ1. However, it does not use IL-12Rβ2. In this study, we identify a novel member of the hemopoietin receptor family as a subunit of the receptor for IL-23, “IL-23R.” IL-23R pairs with IL-12Rβ1 to confer IL-23 responsiveness on cells expressing both subunits. Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R. Anti-IL-12Rβ1 and anti-IL-23R Abs block IL-23 responses of an NK cell line and Ba/F3 cells expressing the two receptor chains. IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3. The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12Rβ2, respectively. The human IL-23R gene is on human chromosome 1 within 150 kb of IL-12Rβ2.