Endotoxin increases parathyroid hormone-related protein mRNA levels in mouse spleen mediation by tumor necrosis factor

Janet L. Funk, Eveline J.T. Krul, Arthur H. Moser, Judy K. Shigenaga, Gordon J. Strewler, Carl Grunfeld, Kenneth R. Feingold

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in malignancy. However, the role and regulation of PTHrP in normal physiology is just beginning to be explored. PTHrP is found in the spleen and has several other features common to cytokines. Since endotoxin (LPS) causes many of its effects indirectly by inducing cytokines, studies were undertaken to determine whether LPS might also induce splenic PTHrP expression. LPS (100 ng/mouse) increased splenic PTHrP mRNA levels 3.6-fold in C3H/OuJ mice. This effect was maximal at 2 h and returned to baseline by 4 h. PTHrP peptide levels also increased 3.3-fold in splenic extracts in response to LPS (1 μg/mouse). Murine TNF-α and human IL-1β, cytokines that mediate many of the effects of LPS, also increased splenic PTHrP mRNA levels. LPS-resistant C3H / HeJ mice, which produce minimal amounts of TNF and IL-1 in response to LPS, were resistant to LPS induction of splenic PTHrP mRNA, while TNF-α and IL-1β readily increased PTHrP mRNA levels in C3H/HeJ mice. Anti-TNF antibody blocked LPS induction of splenic PTHrP mRNA in C3H /OuJ mice by 68%, indicating that TNF is a mediator of the LPS induction of PTHrP levels. In contrast, an IL-1 receptor antagonist (IL-1ra) was ineffective. The increase in PTHrP in the spleen during the immune response suggests that PTHrP may play an important role in immune modulation, perhaps by mediating changes in lymphocyte proliferation and/or function.

Original languageEnglish (US)
Pages (from-to)2546-2552
Number of pages7
JournalJournal of Clinical Investigation
Volume92
Issue number5
DOIs
StatePublished - 1993

Keywords

  • Endotoxin
  • Interleukin-1
  • Lipopolysaccharide
  • Parathyroid hormone-related protein
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Medicine(all)

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