Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase

J Clin Invest. 1993 Sep;92(3):1564-71. doi: 10.1172/JCI116737.

Abstract

The potential involvement of reactive oxygen species in the expression of genes involved in immune response was examined in mesangial cells. Tumor necrosis factor (TNF-alpha) and aggregated (aggr.) IgG increased mRNA levels for the monocyte chemoattractant protein, JE/MCP-1, and the colony-stimulating factor, CSF-1. Scavengers for free radicals such as di- and tetra-methylthiourea (DMTU and TMTU) attenuated the increase in mRNA levels in response to TNF-alpha and aggr. IgG. Generation of superoxide anion by xanthine oxidase and hypoxanthine increased mRNA levels of these genes, but exogenous H2O2 did not. Addition of NADPH to activate a membrane-bound NADPH-oxidase generated superoxide and caused a dose-dependent increase in mRNA levels and further enhanced the stimulation by TNF-alpha or aggr. IgG. An inhibitor of NADPH-dependent oxidase 4'-hydroxy-3'-methoxy-acetophenone attenuated the rise in mRNA levels in response to TNF-alpha and aggr. IgG. By nuclear run-on experiments TNF-alpha, aggr. IgG and NADPH increased the transcription rates for JE/MCP-1 and CSF-1, effects inhibited by TMTU. We conclude that generation of reactive oxygen species, possibly by NADPH-dependent oxidase, are involved in the induction of the JE/MCP-1 and CSF-1 genes by TNF-alpha and IgG complexes. The concerted expression of leukocyte-directed cytokines represents a general response to tissue injury.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemokine CCL2
  • Chemotactic Factors / genetics
  • Chemotactic Factors / metabolism*
  • Gene Expression / drug effects
  • Glomerular Mesangium / metabolism*
  • Hydrogen Peroxide / metabolism
  • Immunoglobulin G / pharmacology*
  • In Vitro Techniques
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Mice
  • NADH, NADPH Oxidoreductases / metabolism*
  • NADP / pharmacology
  • NADPH Oxidases
  • RNA, Messenger / genetics
  • Reactive Oxygen Species / metabolism*
  • Second Messenger Systems
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Chemokine CCL2
  • Chemotactic Factors
  • Immunoglobulin G
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • NADP
  • Macrophage Colony-Stimulating Factor
  • Hydrogen Peroxide
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidases