Interleukin-35

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for induction, course and control of T-cell-mediated cytotoxic immune reactions as well as B-cell activation (antibody production). They are mainly formed and secreted by stimulated leukocytes, monocytes and macrophages. So far, about 38 different interleukins have been clearly identified. Each cytokine of the interleukin group is nomenclatically assigned a number for its classification (IL-1 to IL-38 - status 2017).

Some structurally related substances have been grouped into families. Their members often have a similar function or participate in the fine regulation of immune reactions. An example is the interleukin-12 family with the interleukins IL-12, IL-23, IL-27, and IL-35.

Interleukin-35 is a dimeric, immunosuppressive protein composed of the two chains IL-12alpha and IL-27beta ("Epstein-Barr virus induced 3" -EBI3). Both chains are encoded by separate genes. In different combinations, the two chains form IL-12, IL-23, IL-27, and IL-35, making interleukin-35 the newest member of the IL-12 cytokine family.

The cytokine is formed and secreted mainly by proinflammatory activated regulatory T cells (Tregs), to a lesser extent by CD8(+)Tregs of Bregs and antigen presenting cells (APCs). Regulatory B cells (Breg), suppress an inflammatory immune response (Egwuagu CE et al.2015). Since Bregs are able to secrete interleukin-35 (iBregs), this partly explains the immunosuppressive effect of this B-cell subpopulation.

IL-35 directly suppresses effector T-cell proliferation and function and inhibits the differentiation of Th17 cells (Song M et al.2016). The cytokine suppresses inflammatory immune responses. Thus, the cytokine is able to induce an infection tolerance.

Regulatory T cells continue to play a major role in tumor suppression. In contrast, an overexpression of interleukin-35 by Tregs inhibits their tumor suppressing effect.

Serum levels of interleukin-35 may be elevated in systemic scleroderma.

1. Cai Z et al (2015) Remission of systemic lupus erythematosus disease activity with regulatory cytokine interleukin (IL)-35 in Murphy Roth's Large (MRL)/lpr mice. Clin Exp Immunol 181:253-266.
2. Egwuagu CE et al (2015) Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases. Crit Rev Immunol 35:49-57.
3. Song M et al (2016) The Immunobiology of Interleukin-35 and Its Regulation and Gene Expression. Adv Exp Med Biol 941:213-225.
4. Tomcik M et al (2015) Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease. Rheumatology (Oxford) 54:2273-2282.
5. Turnis ME et al (2016) Interleukin-35 Limits Anti-Tumor Immunity. Immunity 44:316-329.