CD14-dependent and CD14-independent signaling pathways in murine macrophages from normal and CD14 knockout mice stimulated with lipopolysaccharide or …

PY Perera, SN Vogel, GR Detore, A Haziot… - Journal of immunology …, 1997 - journals.aai.org
PY Perera, SN Vogel, GR Detore, A Haziot, SM Goyert
Journal of immunology (Baltimore, Md.: 1950), 1997journals.aai.org
The antitumor agent, Taxol, shares with bacterial LPS the ability to activate murine
macrophages, and its LPS-mimetic effects are blocked by LPS analogue antagonists. Since
CD14 is central to the recognition of LPS by macrophages, we sought to examine a role for
CD14 in the response to Taxol vs LPS. A comparison of responses of macrophages from
wild-type mice with those from mice lacking CD14 due to a targeted disruption of the CD14
gene (CD14-deficient knockout (CD14KO)) revealed that like LPS, Taxol induces both CD14 …
Abstract
The antitumor agent, Taxol, shares with bacterial LPS the ability to activate murine macrophages, and its LPS-mimetic effects are blocked by LPS analogue antagonists. Since CD14 is central to the recognition of LPS by macrophages, we sought to examine a role for CD14 in the response to Taxol vs LPS. A comparison of responses of macrophages from wild-type mice with those from mice lacking CD14 due to a targeted disruption of the CD14 gene (CD14-deficient knockout (CD14KO)) revealed that like LPS, Taxol induces both CD14-dependent and -independent pathways of gene activation, although the CD14 dependency of Taxol stimulation is much less striking than that observed with LPS. The macrophage interaction with low concentrations of LPS (< or = 10 ng/ml) is largely CD14 dependent, as evidenced by the lack of induction of TNF-alpha, IL-1beta, and interferon-inducible protein-10 (IP-10) genes by CD14KO macrophages cultured in the absence of soluble CD14 (i.e., in autologous CD14KO -/- mouse serum). However, at high concentrations of LPS or Taxol, a CD14-independent pathway of activation is observed: this pathway leads to minimal IP-10 gene induction, even though induction of TNF-alpha and IL-1beta occurs. Measurements of TNF secretion followed a similar pattern to that observed at the level of steady state mRNA. These data suggest the existence of two pathways of activation by both LPS and Taxol: one that is CD14 dependent and leads to induction of TNF-alpha, IL-1beta, and IP-10 gene induction, and a CD14-independent pathway that results in the induction of TNF-alpha and IL-1beta, with minimal induction of IP-10.
journals.aai.org