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

Abstract

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.

• Authors: Zhijie Wu, Valentina Giudice, Jichun Chen, Wanling Sun, Zenghua Lin, Keyvan Keyvanfar, Nidhi Talasani, Sachiko Kajigaya, Xingmin Feng, Neal S Young
• Journal: Experimental hematology (Exp Hematol) Vol. 69 Pg. 54-64.e2 (01 2019) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 30316805 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• IFNG protein, human
• IFNG protein, mouse
• IL18R1 protein, human
• IL6 protein, human
• Il18r1 protein, mouse
• Interleukin-18
• Interleukin-18 Receptor alpha Subunit
• Interleukin-6
• Tumor Necrosis Factor-alpha
• interleukin-6, mouse
• Interferon-gamma

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Anemia, Aplastic (genetics, immunology, pathology)
• Animals
• Child
• Child, Preschool
• Disease Models, Animal
• Female
• Hematopoietic Stem Cells (metabolism, pathology)
• Humans
• Interferon-gamma (genetics, immunology)
• Interleukin-18 (genetics, immunology)
• Interleukin-18 Receptor alpha Subunit (genetics, immunology)
• Interleukin-6 (genetics, immunology)
• Male
• Mice
• Middle Aged
• T-Lymphocytes, Helper-Inducer (immunology, pathology)
• Tumor Necrosis Factor-alpha (genetics, immunology)