Interleukin-32beta propagates vascular inflammation and exacerbates sepsis in a mouse model.

Abstract

BACKGROUND: Inflammation is associated with most diseases, which makes understanding the mechanisms of inflammation vitally important. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate a critical function of interleukin-32beta (IL-32beta) in vascular inflammation. IL-32beta is present in tissues from humans, but is absent in rodents. We found that the gene is highly expressed in endothelial cells. Three isoforms of IL-32, named IL-32alpha, beta, and epsilon, were cloned from human endothelial cells, with IL-32beta being the major isoform. Pro-inflammatory cytokines (TNFalpha and IL-1beta) induced IL-32beta expression through NF-kappaB. Conversely, IL-32beta propagated vascular inflammation via induction of vascular cell adhesion molecules and inflammatory cytokines. Accordingly, IL-32beta increased adhesion of inflammatory cells to activated endothelial cells, a paramount process in inflammation. These results illustrate a positive feedback regulation that intensifies and prolongs inflammation. Importantly, endothelial/hematopoietic expression of IL-32beta in transgenic mice elevated inflammation and worsened sepsis. This was demonstrated by significant elevation of leukocyte infiltration and serum levels of TNFalpha and IL-1beta, increased vascular permeability and lung damage, and accelerated animal death. Together, our results reveal an important function of IL-32 in vascular inflammation and sepsis development. CONCLUSIONS/SIGNIFICANCE: Our results reveal an important function of IL-32 in vascular inflammation and sepsis development.