title: Wingless-type mammary tumor virus integration site family, member 5A (Wnt5a) regulates human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120)-induced expression of pro-inflammatory cytokines via the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and c-Jun N-terminal kinase (JNK) signaling pathways.
abstract: BACKGROUND
  HIV-1 infection causes chronic neuroinflammation in the central nervous system (CNS).
  
  
  RESULTS
  The spinal cytokine up-regulation induced by HIV-1 gp120 protein depends on Wnt5a/CaMKII and/or Wnt5a/JNK pathways.
  
  
  CONCLUSIONS
  gp120 stimulates cytokine expression in the spinal cord dorsal horn by activating Wnt5a signaling.
  
  
  CONCLUSIONS
  The finding reveals Wnt signaling-mediated novel mechanisms by which HIV-1 may cause neuroinflammation. Chronic expression of pro-inflammatory cytokines critically contributes to the pathogenesis of HIV-associated neurological disorders (HANDs), but the host mechanism that regulates the HIV-induced cytokine expression in the CNS remains elusive. Here, we present evidence for a crucial role of Wnt5a signaling in the expression of pro-inflammatory cytokines in the spinal cord induced by a major HIV-envelope protein, gp120. Wnt5a is mainly expressed in spinal neurons, and rapidly up-regulated by intrathecal injection (i.t.) of gp120. We show that inhibition of Wnt5a by specific antagonists blocks gp120-induced up-regulation of IL-1β, IL-6, and TNF-α in the spinal cord. Conversely, injection (i.t.) of purified recombinant Wnt5a stimulates the expression of these cytokines. To elucidate the role of the Wnt5a-regulated signaling pathways in gp120-induced cytokine expression, we have focused on CaMKII and JNKs, the well characterized down-stream targets of Wnt5a signaling. We find that Wnt5a is required for gp120 to activate CaMKII and JNK signaling. Furthermore, we demonstrate that the Wnt5a/CaMKII pathway is critical for the gp120-induced expression of IL-1β, whereas the Wnt5a/JNK pathway is for TNF-α expression. Meanwhile, the expression of IL-6 is co-regulated by both pathways. These results collectively suggest that Wnt5a signaling cascades play a crucial role in the regulation of gp120-induced expression of pro-inflammatory cytokines in the CNS.
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Shi
authors.forename: Jianhong
authors.initials: J
authors.lastname: Shu
authors.forename: Junling
authors.initials: J
authors.lastname: Gao
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Shao-Jun
authors.initials: SJ
authors.lastname: Tang
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D016207:Cytokines; D015699:HIV Envelope Protein gp120; D018836:Inflammation Mediators; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C514793:gp120 protein, Human immunodeficiency virus 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048031:JNK Mitogen-Activated Protein Kinases
keywords: CNS; Cytokine; HIV-1; Neurobiology; Neuroinflammation; Spinal Cord; Wnt Signaling; gp120
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