Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease

doi:10.1016/j.cyto.2015.01.030

Cytokine

Volume 75, Issue 2, October 2015, Pages 249-255

https://doi.org/10.1016/j.cyto.2015.01.030 Get rights and content

Highlights

•
We describe a regulatory B cell (Breg) population that produces IL-35 (i35-Breg).
•
Interleukin 35 induces in-vivo and ex-vivo the IL-35-producing B cell (i35-Breg).
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IL-35 induces regulatory B cells that suppress CNS autoimmune disease.
•
Ex-vivo generated Bregs and i35 Bregs suppress ocular inflammation and uveitis.
•
Treatment of experimental uveitis with a novel IL-27p28/IL-12p40 fusokine.

Abstract

Cytokines play crucial roles in coordinating the activities of innate and adaptive immune systems. In response to pathogen recognition, innate immune cells secrete cytokines that inform the adaptive immune system about the nature of the pathogen and instruct naïve T cells to differentiate into the appropriate T cell subtypes required to clear the infection. These include Interleukins, Interferons and other immune-regulatory cytokines that exhibit remarkable functional redundancy and pleiotropic effects. The focus of this review, however, is on the enigmatic Interleukin 12 (IL-12) family of cytokines. This family of cytokines plays crucial roles in shaping immune responses during antigen presentation and influence cell-fate decisions of differentiating naïve T cells. They also play essential roles in regulating functions of a variety of effector cells, making IL-12 family cytokines important therapeutic targets or agents in a number of inflammatory diseases, such as the CNS autoimmune diseases, uveitis and multiple sclerosis.

Introduction

Interleukin 12 (IL-12) family is comprised of 4 members, IL-12, IL-23, IL-27 and IL-35. IL-12, IL-23 and IL-27 are secreted by activated antigen presenting cells (APC) during antigen presentation to naïve T cells while IL-35 is a product of regulatory T and B cells [1], [2], [3]. They provide the bridge between innate and adaptive immune systems by priming naïve CD4⁺ T cells to differentiate into cytokine-producing T-helper subsets and memory T cells [4]. In addition to their influence on cell-fate decisions of differentiating lymphocytes, IL-12 cytokines regulate cellular pathways required for proper functioning of the immune system, with some members activating pro-inflammatory responses that confer protection against infection while others restrain unbridled immune responses that cause autoimmune diseases [1], [5], [6]. This review focuses on signaling pathways activated by IL-12 cytokines and their contribution to the development and regulation of CNS inflammatory diseases, with particular emphasis on ocular inflammatory diseases and to a lesser extent multiple sclerosis (MS). We highlight recent developments in the use of bioengineered IL-12 cytokines and autologous regulatory B cells for the treatment of CNS inflammatory diseases.

Section snippets

Interleukin 12 (IL-12) cytokines

The IL-12 family of cytokines is comprised of IL-12 (IL-12p35/IL-12p40), IL-23 (IL-23p19/IL-12p40), IL-27 (IL-27p28/Ebi3) and IL-35 (IL-12p35/Ebi3) and has emerged as important regulators of host immunity [6], [7]. Each member is composed of α-subunit with a helical structure similar to type 1 cytokines like IL-6 and a β-subunit structurally related to the extracellular regions of Type 1 cytokine receptors (e.g. soluble IL-6 receptor) [6], [7]. The α subunits are IL-12p35, IL-23p19 and IL-27p28

Current strategies for treatment of CNS autoimmune diseases

Therapeutic intervention in CNS autoimmune diseases, such as, uveitis and multiple sclerosis presents formidable challenges due to the need to prevent unbridled immune responses that can damage sensitive neuronal tissues. Data from the clinic and animal models form the basis of our current therapeutic strategies for the treatment of inflammatory and autoimmune diseases. These include: (i) inhibition of T-lymphocyte activity by a variety of humanized antibodies [Zenapax® or daclizumab

Targeting Th17 and Th17 pathways

There is now an emerging consensus of the critical role of Type 17 cells in etiology of several human autoimmune diseases. Prolonged stimulation of these cells promotes EAE, collagen-induced arthritis (CIA) and colitis while mice deficient in type 17 signature genes are relatively resistant to the development of these diseases [22]. The Type 17 cells include the Th17 subset, γ/δ T cells, natural killer T (NKT) cells and innate lymphoid cells (ILCs). They are characterized by expression of the

IL-12 family proteins as therapeutic agents

Promiscuous chain sharing is an important attribute that enables IL-12 family cytokines to participate in many aspects of host immunity. The shared structural features of the single chain IL-12 proteins and their capacity potential to interact with different molecular partners during the course of an immune response, allow different immune cells to interpret seemingly similar cytokine signals that might promote inflammation or immunologic tolerance. The individual IL-12 α or β subunits also

Conclusion

In this review, we have summarized results of recent studies showing that IL-35 and the transfer of ex-vivo generated Bregs and i35-Bregs can be used to treat uveitis, an organ-specific autoimmune disease of the CNS. We have also discussed the use of the novel bioengineered IL-27p28/IL-12p40 cytokine and the IL-12 single-chain protein, IL-27p28, to treat autoimmune uveitis (Table 2). The finding that IL-12p35 and Ebi3 inhibit lymphocyte proliferation but cannot induce expansion of Breg or Treg

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Published by Elsevier Ltd.

Review ArticleInterleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease

Highlights

Abstract

Introduction

Section snippets

Interleukin 12 (IL-12) cytokines

Current strategies for treatment of CNS autoimmune diseases

Targeting Th17 and Th17 pathways

IL-12 family proteins as therapeutic agents

Conclusion

Immunity

Immunity

J Biol Chem

Ophthalmology

J Neuroimmunol

Am J Ophthalmol

Lancet Neurol

Immunity

Am J Hum Genet

Cytokine

Semin Immunol

J Biol Chem

The inhibitory cytokine IL-35 contributes to regulatory T-cell function

Nature

Interleukin-35 induces regulatory B cells that suppress autoimmune disease

Nat Med

IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases

Nature

New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions

Nat Rev

IL-12 family cytokines: immunological playmakers

Nat Immunol

Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells

J Immunol

Interleukin-35: odd one out or part of the family?

Immunol Rev

New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions

Nat Rev Immunol

Expression of murine IL-12 is regulated by translational control of the p35 subunit

J Immunol

Stats: transcriptional control and biological impact

Nat Rev Mol Cell Biol

Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand

Proc Natl Acad Sci USA

Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy

J Clin Invest

Possible roles of IL-12-family cytokines in rheumatoid arthritis

Nat Rev Rheumatol

Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis

J Immunol

Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation

Annu Rev Immunol

The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing

Nat Rev Immunol

Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category

J Exp Med

Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

Nature

IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis

J Clin Invest

Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12

J Clin Invest

IL-23 receptor expression on gammadelta T cells correlates with their enhancing or suppressive effects on autoreactive T cells in experimental autoimmune uveitis

J Immunol

Epstein–Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin

Proc Natl Acad Sci USA

Understanding the pro- and anti-inflammatory properties of IL-27

J Immunol

Review Article
Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease