Recombinant guinea pig tumor necrosis factor alpha stimulates the expression of interleukin-12 and the inhibition of Mycobacterium tuberculosis growth in macrophages

Hyosun Cho, Todd M. Lasco, Shannon Sedberry Allen, Teizo Yoshimura, David N. McMurray

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Tumor necrosis factor alpha (TNF-α) plays an important role in the host immune response to infection with the intracellular pathogen Mycobacterium tuberculosis. It is essential for the formation of protective tuberculous granulomas and regulates the expression of other cytokines which contribute to a protective immune response. Interleukin-12 (IL-12) is known to promote a Th1 response, which is essential for antimycobacterial resistance. Recombinant guinea pig TNFα (rgpTNF-α) protein (17 kDa) was purified, and its bioactivity was confirmed by its cytotoxicity for L929 fibroblasts. High titers of polyclonal anti-gpTNF-α antibody were obtained by immunization of rabbits. Resident alveolar and peritoneal macrophages were isolated from guinea pigs and infected with either the H37Ra or H37Rv strain of M. tuberculosis. The mRNA levels for TNF-α and IL-12 p40 were measured using real-time PCR. IL-12 p40 mRNA was up-regulated in a dose-dependent manner by rgpTNF-α alone. In infected macrophages, a lower dose of rgpTNF-α intensified the mRNA levels of TNF-α and IL-12 p40. However, higher doses of rgpTNF-α suppressed TNF-α and IL-12 p40 mRNA. The antimycobacterial activity of macrophages was assessed by metabolic labeling of M. tuberculosis with [3H]uracil. Resident alveolar and peritoneal macrophages treated with anti-gpTNF-α antibody to block endogenous TNF-α exhibited increased intracellular mycobacterial growth. These data suggest that the dose of TNF-α is crucial to the stimulation of optimal expression of protective cytokines and that TNF-α contributes to the control of mycobacterial replication to promote host resistance against M. tuberculosis.

Original languageEnglish
Pages (from-to)1367-1376
Number of pages10
JournalInfection and Immunity
Volume73
Issue number3
DOIs
Publication statusPublished - Mar 2005

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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