Other
16 Authors
- Quan N,
- Le X,
- DiSabato DJ,
- Li J,
- Nemeth DP,
- Chen Z,
- Wu D,
- Godbout JP,
- Oliver B,
- Witcher KG,
- Mckim DB,
- Berdysz O,
- Ramani AD,
- Liu X,
- Gorantla G,
- Zhu L
| First Author | Zhu L | Year | 2019 |
| Journal | Brain Behav Immun | Volume | 81 |
| Pages | 292-304 | PubMed ID | 31228609 |
| Mgi Jnum | J:286472 | Mgi Id | MGI:6390001 |
| Doi | 10.1016/j.bbi.2019.06.026 | Citation | Zhu L, et al. (2019) Interleukin-1 causes CNS inflammatory cytokine expression via endothelia-microglia bi-cellular signaling. Brain Behav Immun 81:292-304 |
| abstractText | As a major producer of the inflammatory cytokine interleukin-1 (IL-1), peripheral macrophages can augment IL-1 expression via type 1 IL-1 receptor (IL-1R1) mediated autocrine self-amplification. In the CNS, microglial cells are the major producers of inflammatory cytokines, but express negligible levels of IL-1R1. In the present study, we showed CNS IL-1 induced microglial proinflammatory cytokine expression was mediated by endothelial, not microglial, IL-1R1. This paracrine mechanism was further dissected in vitro. IL-1 was unable to stimulate inflammatory cytokine expression directly from the microglial cell line BV-2, but it stimulated the brain endothelial cell line bEnd.3 to produce a factor(s) in the culture supernatant, which was capable of inducing inflammatory cytokine expression in BV-2. We termed this factor IL-1-induced microglial activation factors (IMAF). BV-2 cytokine expression was inducible by extracellular ATP, but IL-1 did not stimulate the release of ATP from bEnd.3 cells. Filtration of IMAF by size-exclusion membranes showed IMAF activity resided in molecules larger than 50kd and incubation of IMAF at 95 degrees C for 5min did not alter its activity. Microglial inhibitor minocycline was unable to block IMAF activity, even though it blocked LPS induced cytokine expression in BV-2 cells. Adding NF-kappaB inhibitor to the bEnd.3 cells abolished IL-1 induced cytokine expression in this bi-cellular system, but adding NF-kappaB inhibitor after IMAF is already produced failed to abrogate IMAF induced cytokine expression in BV-2 cells. RNA sequencing of IL-1 stimulated endothelial cells revealed increased expression of genes involved in the production and processing of hyaluronic acid (HA), suggesting HA as a candidate of IMAF. Inhibition of hyaluronidase by ascorbyl palmitate (AP) abolished IMAF-induced cytokine expression in BV-2 cells. AP administration in vivo also inhibited ICV IL-1-induced IL-1 expression in the hippocampus and hypothalamus. In vitro, either TLR2 or TLR4 inhibitors blocked IMAF induced BV-2 cytokine expression. In vivo, however, IL-1 induced cytokine expression persisted in either TLR2 or TLR4 knockouts. These results demonstrate IL-1 induced inflammatory cytokine expression in the CNS requires a bi-cellular system and HA could be a candidate for IMAF. |
