Interaction between heat shock and interleukin 6 stimulation in the acute-phase response of human hepatoma (HepG2) cells

Authors

  • Jens O. Karlsson,

    1. Department of Mechanical Engineering, University of Illinois, Chicago, IL
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  • Martin L. Yarmush,

    1. Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School
    2. Shriners Burns Hospital, Boston, MA
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  • Mehmet Toner M.D.

    Corresponding author
    1. Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School
    2. Shriners Burns Hospital, Boston, MA
    • Shriners Research Center, One Kendall Square, 1400W, Cambridge, MA 02139. Fax: (617) 374-5665
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Abstract

Two characteristic elements of the acute-phase response are an altered pattern of circulating hepatic proteins and fever. Whereas a fever-induced heat shock response could affect expression of acute-phase proteins in the liver, the effects of a modest temperature increase on protein secretion in interleukin-6 (IL-6)–stimulated HepG2 cells were investigated. The response of HepG2 cells to IL-6 stimulation was significantly affected by heat treatment at 40°C. Albumin secretion rates, which were reduced by a factor of 2 in response to either heat shock or IL-6 stimulation alone, were down-regulated by a factor of 4 when IL-6 was administered simultaneously with a continuous 40°C heat shock. IL-6–induced fibrinogen up-regulation was significantly reduced by heat treatment (P < .01), and secretion rates were indistinguishable from control levels after 2 days (P > .10). Unexpectedly, heat shock at 40°C induced a fivefold up-regulation of haptoglobin production in the absence of IL-6. Simultaneous heat shock and IL-6 stimulation caused a synergistic enhancement of haptoglobin expression, with secretion rates increasing up to 30-fold compared with unstimulated control cells. For all three proteins, the interaction between temperature and IL-6 concentration was statistically significant (P < .001). Heat treatment resulted in significant alterations of both the kinetics and sensitivity of IL-6–induced protein synthesis, suggesting a major modification of the mechanism of acute-phase protein regulation at 40°C. In summary, the data show that heat shock can significantly modulate the pattern of acute-phase protein expression and that fever may be an important regulatory factor in the acute-phase response.

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