Elsevier

Experimental Hematology

Volume 69, January 2019, Pages 54-64.e2
Experimental Hematology

Interleukin-18 plays a dispensable role in murine and likely also human bone marrow failure

https://doi.org/10.1016/j.exphem.2018.10.003Get rights and content
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Highlights

  • Interleukin-18 (IL-18) and IL-18 binding protein (IL-18BP) levels were significantly elevated in severe aplastic anemia (SAA) patients.

  • IL-18 receptor (IL-18R) was expressed on human hematopoietic stem and progenitor cells (HSPCs).

  • Culturing human CD34+ cells with IL-18 perturbed gene expression in hematopoiesis.

  • Disruption of the IL-18/IL-18R signaling pathway did not alleviate murine bone marrow (BM) failure.

Interleukin-18 (IL-18), also known as interferon-gamma (IFN-γ)-inducing factor, is involved in Th1 responses and regulation of immunity. Accumulating evidence implicates IL-18 in autoimmune diseases, but little is known of its role in acquired aplastic anemia (AA), the immune-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). IL-18 protein levels were significantly elevated in sera of severe AA (SAA) patients, including both responders and nonresponders assayed before treatment, and decreased after treatment. IL-18 receptor (IL-18R) was expressed on HSPCs. Co-culture of human BM CD34+ cells from healthy donors with IL-18 upregulated genes in the helper T-cell and Notch signaling pathways and downregulated genes in the cell cycle regulation, telomerase, and IL-6 signaling pathways. Plasma IL-18 levels were also elevated in murine models of immune-mediated BM failure. However, deletion of IL-18 in donor lymph node cells or deletions of either IL-18 or IL-18R in recipients did not attenuate elevations of circulating IFN-γ, tumor necrosis factor-alpha, or IL-6, nor did they alleviate BM failure. In summary, our findings suggest that, although increased circulating IL-18 is a feature of SAA, it may reflect an aberrant immune response but be dispensable to the pathogenesis of AA.

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