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,
,
* Program in Molecular Medicine and Departments of
Internal Medicine/Infectious Diseases,
Biochemistry, and
Microbiology and Immunology, Wake Forest University Medical Center, Winston-Salem, NC 27157; and
¶ Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany
Human Toll-like receptor (TLR) 4 and TLR2 receptors recognize LPS
or lipoteichoic acid (LTA), respectively. Prolonged exposure of human
macrophages/monocytes to bacterial LPS induces a state of
adaptation/tolerance to subsequent LPS challenge. Inflammatory gene
expressions such as IL-1
and TNF-
are selectively repressed,
while certain anti-inflammatory genes such as secretory IL-1R
antagonist are still induced in LPS-adapted/tolerant cells. In this
report, we demonstrate that LPS-tolerized human promonocytic THP-1
cells develop cross-tolerance and no longer respond to LTA-induced
IL-1/TNF- production, indicating that disruption of common
intracellular signaling is responsible for the decreased
IL-1/TNF- production. We observe that down-regulation of
IL-1R-associated kinase (IRAK) protein level and kinase activity
closely correlates with the development of cross-tolerance. IRAK
protein levels and kinase activities in LPS-tolerized cells remain low
and hyporesponsive to subsequent LPS or LTA challenges. We also
demonstrate that THP-1 cells with prolonged LTA treatment develop LTA
tolerance and do not express IL-1/TNF- upon further LTA
challenge. Strikingly, cells tolerized with LTA are only refractory to
subsequent LTA challenge and can still respond to LPS stimulation.
Correspondingly, stimulation of TLR2 by LTA, although activating IRAK,
does not cause IRAK degradation. IRAK from LTA-tolerized cells can be
subsequently activated and degraded by further LPS challenge, but not
LTA treatment. Our studies reveal that LTA-induced tolerance is
distinct compared with that of LPS tolerance, and is likely due to
disruption of unique TLR2 signaling components upstream of
MyD88/IRAK.
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