Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes

Toxicol Appl Pharmacol. 2014 Oct 1;280(1):42-52. doi: 10.1016/j.taap.2014.07.010. Epub 2014 Jul 23.

Abstract

HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes.

Keywords: AP-1; Astrocyte; HO-1; Inflammation; NF-κB; Tat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Cell Line
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Enzyme Induction / physiology
  • Heme Oxygenase-1 / biosynthesis*
  • Humans
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Pentacyclic Triterpenes
  • Transcription Factor AP-1 / antagonists & inhibitors*
  • Transcription Factor AP-1 / metabolism
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*
  • tat Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors
  • tat Gene Products, Human Immunodeficiency Virus / toxicity*

Substances

  • Anti-Inflammatory Agents
  • NF-kappa B
  • Pentacyclic Triterpenes
  • Transcription Factor AP-1
  • Triterpenes
  • tat Gene Products, Human Immunodeficiency Virus
  • Heme Oxygenase-1
  • celastrol