40 Inflammation & Allergy - Drug Targets, 2009, 8, 40-52 1871-5281/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. The IL-12 Family of Cytokines in Infection, Inflammation and Autoimmune Disorders Katrina Gee 1 , Christina Guzzo 1 , Nor Fazila Che Mat 1 , Wei Ma 2 and Ashok Kumar *,2 1 Department of Microbiology and Immunology, Queen’s University, Kingston ON, Canada 2 Division of Virology, Department of Pathology and Laboratory Medicine, and Research Institute; Children’s Hospital of Eastern Ontario, University of Ottawa, Ontario, Canada Abstract: Cytokines are critical coordinators of the immune response necessary for resolving bacterial and viral assaults on the immune system. In particular, the IL-12 family of cytokines are key players in the regulation of T cell responses. These responses are orchestrated by monocytes, macrophages, and dendritic cells which produce the members of the IL- 12 family of cytokines in response to infection. IL-27 and IL-23 are two cytokines that are related to IL-12; these cytoki- nes share homology at the subunit, receptor, and signalling levels. IL-12 is composed of p35 and p40 subunits, which, when combined together form the bioactive IL-12p70. IL-23 is composed of the IL-12p40 subunit as well as the IL-23p19 subunit, which shares homology with IL-12p35. IL-27 is composed of EBI3 and p28. These three cytokines activate simi- lar members of the JAK/STAT signalling pathways as a result of homology in their receptor components. Production of these cytokines by activated monocytes, macrophages, and dendritic cells results in the activation and differentiation of T cells. In spite of their similarity, each of these cytokines has specific roles in the regulation of immune responses. IL-12 is required for the induction of IFN- production, critical for the induction of Th1 cells. IL-27 has been shown to play a role in the induction of Th1 cells from naive T cells, whereas IL-23 has been demonstrated to play a key role in the induction of the newly described Th17 cells. Recently, a novel heterodimeric and anti-inflammatory cytokine composed of the IL- 12p35 and EBI3 subunits has been identified as IL-35. The biological properties of the IL-12 family of cytokines, the sig- nalling pathways mediated by these cytokines and their role in infection, inflammation, and autoimmune diseases will be the focus of this review. INTRODUCTION The IL-12 family of cytokines are responsible for the generation of Th1 T cells and secretion of IL-12 has been linked with innate immunity as well as the development of adaptive immunity characterized by the induction of IFN- production. IL-12 is composed of two covalently linked subunits, IL-12p35 and IL-12p40. When expressed together, the bioactive IL-12p70 is formed. Recently, two new mem- bers of IL-12 family cytokines have been characterized, namely IL-23 and IL-27 [1, 2]. IL-23 is composed of two covalently linked subunits: IL-23p19, which is distantly re- lated to IL-12p35, and the IL-12p40 subunit. Expression of the two subunits has been deemed to be tightly regulated and IL-23p19 is poorly secreted in the absence of IL-12p40 [3]. Similar to IL-12, IL-23 is capable of binding to the IL- 12R1 however it does not bind IL-12R2. A second IL-23 receptor subunit, IL-23R was identified [4]. IL-23 affects the activation of memory T cells, and plays a crucial role in the generation of the Th17 lineage of T cells. IL-27 was first identified in 2002 by Pflanz et al. and is a heterodimeric cyto- kine composed of an IL-27p28 (p28) and Epstein Barr virus induced gene 3 (EBI3) subunits [5-8]. The p28 subunit, like IL-12p35, is a four helical cytokine subunit, whereas EBI3 structurally resembles the p40 subunit of IL-12 and shares homology with IL-6R [8, 9]. Although similar to IL-12 and *Address correspondence to this author at the Departments of Pathology and Laboratory Medicine, Division of Virology and Molecular Immunology, Research Institute, Children’s Hospital of Eastern Ontario, University of Ottawa, 401 Smyth Road, Ottawa, Ontario, Canada; Tel: 613-737-7600, Ext. 3920; E-mail: akumar@uottawa.ca IL-23 structurally, IL-27 is unique in that the p28 and EBI3 are not held together by disulphide bonds [8, 10]. The ab- sence of a disulphide bond imparts the possibility for the two subunits to be produced by different cells and associate ex- tracellularly. However, efficient bioactive IL-27 expression requires that both subunits be secreted from the same cell [8]. IL-27 functions to activate naive T cells and also modu- lates pro- and anti-inflammatory activities. IL-35, composed of the IL-12p35 and IL-27 EBI3 subunits, was recently iden- tified to play a role in suppression of inflammation via its secretion by T regulatory cells [11-15]. OVERVIEW OF IL-12 AND IL-12-INDUCED SIG- NALLING PATHWAYS IL-12 is produced primarily by monocytes, macrophages, dendritic cells (DCs), and B cells. The major functions of IL- 12 include induction of IFN- production from natural killer (NK) cells and T cells, enhancement of cytotoxity of NK and cytotoxic T cells (CTL), and differentiation of naïve T cells into Th1 effectors, suggesting a key role for IL-12 in the development of cell-mediated immunity (CMI) [16, 17]. The genes encoding the human IL-12p40 and IL-12p35 subunits map to chromosomes 5q31-32 and 3q13.2, respectively, and bear no apparent homology [18]. However, p35 shares ho- mology with other single-chain cytokines such as IL-6 [19], whereas p40 is homologous to the hematopoietin receptor family, particularly the extracellular domain of the IL-6R chain [20]. The genes encoding the murine and human p40 and p35 exhibit 70 and 60% sequence homology, respec- tively [12]. IL-12p40 is expressed and secreted as monomer and homodimer [21, 22]. The p40 monomer seems to have