The IL-12 Cytokine and Receptor Family in Graft-vs.-Host Disease

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is performed with curative intent for high- risk blood cancers and bone marrow failure syndromes; yet the development of acute and chronic graft-vs.-host disease (GVHD) remain preeminent causes of death and morbidity. The IL-12 family of cytokines is comprised of IL-12, IL-23, IL-27, IL-35, and IL-39. This family of cytokines is biologically distinct in that they are composed of functional heterodimers, which bind to cognate heterodimeric receptor chains expressed on T cells. Of these, IL-12 and IL-23 share a common β cytokine subunit, p40, as well as a receptor chain: IL-12Rβ1. IL-12 and IL-23 have been documented as proinflammatory mediators of GVHD, responsible for T helper 1 (Th1) differentiation and T helper 17 (Th17) stabilization, respectively. The role of IL-27 is less defined, seemingly immune suppressive via IL-10 secretion by Type 1 regulatory (Tr1) cells yet promoting inflammation through impairing CD4 + T regulatory (Treg) development and/or enhancing Th1 differentiation. More recently, IL-35 was described as a potent anti-inflammatory agent produced by regulatory B and T cells. The role of the newest member, IL-39, has been implicated in proinflammatory B cell responses but has not been explored in the context of allo-HCT. This review is directed at discussing the current literature relevant to each IL-12-family cytokine and cognate receptor engagement, as well as the consequential downstream signaling implications, during GVHD pathogenesis. Additionally, we will provide an overview of translational strategies targeting the IL-12 family cytokines, their receptors, and subsequent signal transduction to control GVHD.

Immunoregulatory Functions of the IL-12 Family of Cytokines in Antiviral Systems

“…IL-12 has a heterodimeric structure comprising an α-subunit (IL-12p35) and a β-subunit (IL-12p40). IL-12 recognizes its receptors, IL-12Rβ1 and IL-12Rβ2, leading to the binding of Non-receptor tyrosine-protein kinase (TYK2) and Janus kinase 2 (JAK2), respectively, mainly in order to induce signal transducer and activator of transcription 4 (STAT4), which is necessary for IL-12 function [2]. Many studies have clearly demonstrated that IL-12 enhances the connection between the innate and adaptive immune responses.…”

“…IL-23 was first described in 2000 by Oppman et al Expression of IL-23 is strongly mediated through its two subunits (IL-23p19 and IL-12p40) because IL-23 shares IL-12p40 with IL-12. When IL-12p35 level is higher than that of IL-23p19, IL-23 production is suppressed [2]. Clusterdifferentiation 40 (CD40) and CD40 ligand (CD40L) stimulate the expression of the two subunits of IL-23 receptors (IL-12R-β1 and IL-23R), which bind to the same proteins (TYK2 and JAK2) as IL-12 to stimulate STAT3 and STAT4 [3].…”

“…IL-27p28 combines with a IL-27R (WSX-1) receptor and Epstein–Barr virus-induced gene3 (EBi3) matches with a gp130 receptor [3]. In this case, JAK1 cooperates with JAK2 to phosphorylate STAT1-STAT3 dimers [2].…”

“…IL-35 shares the IL-12p35 subunit with IL-12, and EBi3 with IL-27 [2]. Interestingly, IL-35 can interact with four different receptor combinations: gp130:IL-12β2, gp130:gp130, IL-12β2:IL-12β2, and IL-12β2:WSX-1 [4].…”

The Expression of IL-12 Family Members in Patients with Hypertension and Its Association with the Occurrence of Carotid Atherosclerosis

“…Unlike other members of the other IL families, the IL-12 family members, namely, IL-12, IL-23, IL-27, and IL-35, are unique, and they all consist of heterogeneous dimers composed of two subunits with the same structural homology [5]. The IL-12 family members can bind to receptors on target organs, activate downstream Janus kinase 1/2-signal transducers and activators of transcription (JAK1/2-STAT1/3/4) pathways, regulate inflammation, and participate in downstream signal regulation [5][6][7]. Despite their similarities in structure, composition, receptors, and signaling pathways, their biological effects are quite different.…”