A Human Dendritic Cell Subset Receptive to the Venezuelan Equine Encephalitis Virus-Derived Replicon Particle Constitutively Expresses IL-32

Abstract

Dendritic cells (DCs) are a diverse population with the capacity to respond to a variety of pathogens. Because of their critical role in pathogenesis and Ag-specific adaptive immune responses, DCs are the focus of extensive study and incorporation into a variety of immunotherapeutic strategies. The diversity of DC subsets imposes a substantial challenge to the successful development of DC-based therapies, requiring identification of the involved subset(s) and the potential roles each contributes to the immunologic responses. The recently developed and promising Venezuelan equine encephalitis replicon particle (VRP) vector system has conserved tropism for a subset of myeloid DCs. This immunotherapeutic vector permits in situ targeting of DCs; however, it targets a restricted subset of DCs, which are heretofore uncharacterized. Using a novel technique, we isolated VRP-receptive and -nonreceptive populations from human monocyte-derived DCs. Comparative gene expression analysis revealed significant differential gene expression, supporting the existence of two distinct DC populations. Further analysis identified constitutive expression of the proinflammatory cytokine IL-32 as a distinguishing characteristic of VRP-receptive DCs. IL-32 transcript was exclusively expressed (>50 fold) in the VRP-receptive DC population relative to the background level of expression in the nonreceptive population. The presence of IL-32 transcript was accompanied by protein expression. These data are the first to identify a subset of immature monocyte-derived DCs constitutively expressing IL-32 and they provide insights into both DC biology and potential mechanisms employed by this potent vector system.

IL-32 is expressed by human primary keratinocytes and modulates keratinocyte apoptosis in atopic dermatitis

“…The cellular source of serum IL-32 in these patients is unclear, but it can be released from apoptotic KCs, or IL-32 could be secreted from other immune cells, such as macrophages, DCs, or T cells, which are involved in the inflammatory process of AD. 9,13,36 Increased IL-32 serum levels in patients with asthma compared with those seen in healthy control subjects or patients with psoriasis support our hypothesis that IL-32 is released from apoptotic cells in vivo. The asthmatic epithelial response shows similarity to AD with increased apoptosis induced by T cells and eosinophils, with IFN-g and TNF-a as key cytokines leading to epithelial cell shedding.…”

IL-32 Promotes Angiogenesis

“…In each of these models, the abundance of IFNs was dependent on the levels of IL-32, but the anti-viral activity of IL-32 was only in part via type I IFNs. IL-32 has also been implicated in the immune response to influenza A (17), hepatitis B (18) and C (19), papillomavirus (20), and the Venezuelan equine encephalitis virus (21). …”

Inhibition of angiogenesis by IL-32: Possible role in asthma

“…16 IL-32 does not belong to a currently known cytokine family, and a receptor for IL- 32 has not yet been described. 17 The IL32 Abbreviations used ECP: Eosinophilic cationic protein HUVEC: Human umbilical vein endothelial cell NHBE: Normal human bronchial epithelial PDGF: Platelet-derived growth factor poly[I:C]: Polyinosinic:polycytidylic acid siRNA: Small interfering RNA TLR: Toll-like receptor Treg: Regulatory T VEGF: Vascular endothelial growth factor gene is expressed by many cells, including T cells, 18 dendritic cells, 19 endothelial cells, 20 and keratinocytes. 21 However, not all these cell types secrete IL-32.…”