IL-26 Plays Antimicrobial Role in Immune Response

Interleukin 17-producing helper T cells (Th17 cells) secrete copious amounts of interleukin 26 (IL-26) in patients with such autoimmune diseases as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Although investigators know that IL-26 levels correlate with Th17-mediated autoimmune disease, they still don’t understand how IL-26 expression by Th17 is regulated. It’s also known that high concentrations of IL-26 are capable of directly killing normal human cells in vitro.

Stephan Meller, PhD, a postdoctoral fellow at the University of Texas MD Anderson Cancer Center in Houston, and colleagues investigated the pro-inflammatory role of IL-26 and published their results in the September 2015 issue of Nature Immunology. They report that IL-26 produced by Th17 cells not only has direct antimicrobial activity, but also triggers the expression of Type I interferon, thereby driving a potent immune response.

The researchers began their investigation by sequencing IL-26, which revealed a molecule with an unusually high positive charge (+18.1) at pH 7. Moreover, they found that IL-26 formed dimers, as well as higher-degree multimers. The potential clustering of cationic charges led the investigators to hypothesize that IL-26 had antimicrobial properties.

“Our findings demonstrate an unexpected function of the human cytokine IL-26 in Th17 cell-mediated antimicrobial and inflammatory responses,” write the authors in their discussion. “As predicted on the basis of its cationicity, amphipathicity and ability to form multimers, IL-26 exerted direct antimicrobial activity against extracellular bacteria. Like classical cationic antimicrobial peptides, IL-26 forms pores in bacterial membranes, which leads to microbial lysis.”

Clustered cationic charges have also been known to form complexes with extracellular DNA Thus, the investigators asked whether IL-26 was able to bind to DNA during bacterial killing. They found IL-26 did indeed form complexes with DNA released by dying bacteria. They next asked whether IL-26 was capable of killing human cells and binding to released self-DNA. They found IL-26 could kill a range of human cells. And surprisingly, natural IL-26 from Th17 supernatants was more potent than recombinant IL-26 at killing human cells. Either way, the IL-26 bound to the DNA released by the dying host cells.

IL-26-DNA complexes then triggered plasmocytoid dendritic cells (pDCs) to produce Type I interferon via activation of toll-like receptor 9 (TLR9). The process was independent of the IL-26 receptor. Thus, IL-26 serves as a potent antimicrobial that promotes the immune sensing of both bacterial and host cell death.

“Although pDCs seem to be the main target of IL-26 DNA complexes, we observed some activation of monocytes that led to the production of small amounts of IFN-α; this suggested broader implication of IL-26 in DNA-mediated innate immune activation, potentially via cytosolic STING-dependent DNA sensors, as described for LL-37. Future studies will be needed to determine whether, like LL-37, IL-26 can bind extracellular RNA fragments and trigger activation of conventional DCs [dendritic cells] and monocytes via TLR8,” they explained in their discussion.

The authors concluded their paper by proposing that modulation of IL-26 function may serve a therapeutic function in autoimmune disease.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

Reference

1. Meller S, Di Domizio J, Voo KS, et al. TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat Immunol. 2015 Sep:16(9):970–9. doi: 10.1038/ni.3211. Epub 2015 Jul 13.