HIV impairs TNF-alpha release in response to Toll-like receptor 4 stimulation in human macrophages in vitro

Am J Respir Cell Mol Biol. 2005 Dec;33(6):610-21. doi: 10.1165/rcmb.2004-0341OC. Epub 2005 Aug 18.


The molecular mechanisms for increased risk of bacterial pneumonia in HIV+ persons remain incompletely understood. Recognizing the critical role of Toll-like receptor (TLR) signaling in host defense, this study showed that human U937 macrophage stimulation by the TLR4-specific ligand, lipid A (biologically active component of bacterial LPS), promoted TNF-alpha release through extracellular regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase phosphorylation. In contrast, HIV+ U1 macrophages had significantly reduced TNF-alpha release (despite preserved TLR4 expression) and reduced ERK1/2 phosphorylation, whereas TNF-alpha release was intact via a TLR4-independent pathway. In HIV+ U1 cells, reduced ERK1/2 phosphorylation was not due to reduced upstream MEK1/2 activation, but was associated with a reciprocal induction of MAP kinase phosphatase-1 (MKP-1). HIV nef protein was sufficient to reduce TNF-alpha release and induce MKP-1 in healthy macrophages. Pharmacologic inhibition of endogenous cellular phosphatases increased ERK1/2 phosphorylation and partially restored TLR4-mediated TNF-alpha release in HIV+ macrophages. Furthermore, targeted gene silencing of MKP-1 partially restored lipid A-mediated TNF-alpha release in HIV+ U1 cells. Similar results were observed using clinically relevant human alveolar macrophages, comparing healthy to asymptomatic HIV+ persons at clinical risk for bacterial pneumonia. Thus, reduced TLR4-mediated TNF-alpha release through altered ERK1/2 regulation by HIV may impair an effective innate immune response to bacterial challenge. Inhibition of cellular phosphatases may serve as a potential therapeutic target in the management of bacterial pneumonia in HIV+ persons.

Publication types

  • Comparative Study

MeSH terms

  • Case-Control Studies
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Dual Specificity Phosphatase 1
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Products, nef / physiology
  • Gene Silencing
  • HIV / physiology*
  • HIV Infections
  • HIV Seropositivity
  • Humans
  • Immediate-Early Proteins / antagonists & inhibitors
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • In Vitro Techniques
  • Lipid A / pharmacology
  • MAP Kinase Kinase 1 / metabolism
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / metabolism
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*
  • U937 Cells
  • nef Gene Products, Human Immunodeficiency Virus
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cell Cycle Proteins
  • Gene Products, nef
  • Immediate-Early Proteins
  • Lipid A
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • nef Gene Products, Human Immunodeficiency Virus
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Protein Tyrosine Phosphatases