Induction of Immunity and Inflammation by Interleukin12 Family Members

G. Alber, S. Al-Robaiy, M. Kleinschek, J. Knauer, P. Krumbholz, J. Richter, S. Schoeneberger, N. Schuetze, S. Schulz, K. Toepfer, R. Voigtlaender, J. Lehmann, U. Mueller

7.1 Structure of IL-12 Family Members 108

7.2 Expression of IL-12 Family Members and Their Receptors 109

7.3 Signal Transduction 111

7.4 Biology of IL-12 Family Members 112

7.5 Role of IL-12 Family Members in Host Defense 114

7.6 Antitumor Activity of IL-12 Family Members 116

7.7 Role of IL-12 Family Members in Organ-Specific Autoimmunity . 117

7.7.1 Experimental Autoimmune Encephalomyelitis 118

7.7.2 Rheumatoid Arthritis 118

7.7.3 Psoriasis Vulgaris 119

7.7.4 Inflammatory Bowel Disease 120

7.7.5 Insulin-Dependent Diabetes Mellitus 121

References 121

Abstract. The interleukin (IL)-12 family is composed of three heterodimeric cytokines, IL-12 (p40p35), IL-23 (p40p19), and IL-27 (EBI3p28), and of monomeric and homodimeric p40. This review focuses on the three heterodimeric members of the IL-12 family. The p40 and p40-like (EBI3) subunits have homology to the IL-6R, the other subunits (p35, p19, and p28) are homologous to each other and to members of the IL-6 superfamily. On the basis of their structural similarity, it was expected that the members of the IL-12 family have overlapping pro-inflammatory and immunoregulatory functions. However, it was surprising that they also show very distinct activities. IL-12 has a central role as a Thl-inducing and -maintaining cytokine, which is essential in cell-mediated immunity in nonviral infections and in tumor control. IL-23 recently emerged as an end-stage effector cytokine responsible for autoimmune chronic inflammation through induction of IL-17 and direct activation of macrophages. Very recently, IL-27 was found to exert not only a pro-inflammatory Thl-enhancing but also a significant anti-inflammatory function.

7.1 Structure of IL-12 Family Members

Interleukin (IL)-12 was discovered as "natural killer cell stimulatory factor (NKSF)" in 1989 (Kobayashi et al. 1989) and by another group as "cytotoxic lymphocyte maturation factor (CLMF)" in 1990 (Stern et al. 1990). It was the first cytokine to be found with a heterodimeric structure (Gately et al. 1998; Trinchieri 1998). IL-12 is composed of a p35 and a p40 subunit. Both subunits are covalently linked. Each subunit is expressed by its own gene, whereby the p35and p40 genes are located on different chromosomes. The sequence of p35 shows homology with that of IL-6 and G-CSF (Merberg et al. 1992) and encodes a p35 subunit that shows a four-a-helix bundle structure typical of cytokines. The sequence of the p40 subunit is homologous to the extracellular portion of members of the hemopoietin receptor family, in particular to the IL-6 receptor a-chain (IL-6Ra) and the ciliary neurotrophic factor receptor (CNTFR) (Gearing and Cosman 1991). Therefore, IL-12 represents a heterodimeric cytokine with one chain (p35) having the actual cytokine structure and the other chain (p40) showing the structure of a cytokine receptor. While IL-12 might have evolved from the IL-6/IL-6R family, it has meanwhile established its own family (Fig. 1). In 2000, a novel p40p19 heterodimeric molecule was found and designated IL-23 (Opp-mann et al. 2000). Only 2 years later, another IL-12 family member termed IL-27 was described, which consists of the p40-like subunit EBI3 noncovalently linked to a p28 subunit (Pflanz et al. 2002). Thus, the novel IL-12 family consists of cytokines with a p40 or a p40-like (EBI3) receptor component together with members of the long-chain four-a-helix bundle cytokine family (p35, p19, and p28) (Fig. 1). This

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