Biology Reference
In-Depth Information
the production of pro-inflammatory cytokines is drastically reduced,
since JNK and NF-κB activation is delayed. Although both the MyD88-
dependent and -independent pathways are active in response to LPS, the
lipid A structure can apparently influence which signaling pathway is
activated (Zughaier
et al.
, 2005). A more thorough discussion of the
TLR4 intracellular signaling pathways can be found in some current
reviews (Akira and Takeda, 2004, Takeda and Akira, 2004).
Internalization of LPS is a critical step in removing the pathogenic
antigen. It has been found that TLR4 does not appear to mediate this
step, although much work remains in order to sort out the specific
receptor(s) involved. Inhibition of TLR4 with a human antibody or using
monocytes from TLR4 knockout mice (C57BL/6) leads to decreased
cytokine output, but does not diminish the accumulation of fluorescently-
labeled LPS inside of the cells (Zhou
et al.
, 2004, Dunzendorfer
et al.
,
2004). Using CD14-deficient murine monocytes confirmed that mCD14
is necessary for LPS uptake. Recent evidence seems to show that
scavenger receptors, known to bind both macromolecules having a
negative charge and modified low-density lipoproteins, are involved in
the uptake of LPS/LBP complexes (Hampton
et al.
, 1991, Shnyra and
Lindberg, 1995, Vishnyakova
et al
., 2003, Seternes
et al.
, 2001).
Monocytes, macrophages, and PMN are among the most active
phagocytic cells. Liver cells, especially Kupffer cells (liver
macrophages) are also very active in the clearance of both bacterial
components and whole bacteria.
Similarly to lipid A, the peptidoglycan (PGN) and lipoteichoic acid
(LTA) of Gram-positive bacteria are recognized by CD14, but unlike
lipid A, this interaction does not play a prominent role in stimulating
TNFα secretion (Haziot
et al.
, 1999). Furthermore, LBP does not
mediate the transfer of LTA or PGN to the CD14 receptor. In contrast to
Gram-negative bacteria, Gram-positive bacterial components such as
LTA and PGN are mainly recognized by TLR2 (Schwandner
et al.
,
1999). However, LTA recognition through TLR4 also has been observed
(Takeuchi
et al.
, 2000). Since TLR2 and TLR4 share a substantial part of
the TLR signaling pathway, binding to either member results in nearly
identical immunological responses involving mostly the same mediators
that are generated by LPS stimulation (TNFα, IL-1β, IL-6, and INF-γ).
