is a key component forming the outer cell membrane of Gram-negative bacteria
and a key stimulus for monocytic cells1. Monocytes organize the
innate immunity in response to LPS detection by expressing and secreting a
range of proinflammatory cytokines including tumour necrosis factor-alpha
(TNF-A), interleukin-1? (IL-1?), and IL-62.
LPS binding to
monocyte is initially mediated by CD14 which is a non-transmembrane antigen and
LPS –binding protein (LBP) which is a serum- derived protein that facilitates
binding of LPS to CD143. CD14 protein is expressed on the surface of
myeloid cells via a glycosylphosphatidylinositol inositol anchor (GPI) which
anchors the protein to the membrane without a transmembrane segment1.
The effect of LPS on cytokine expression in monocytic cell lines is also
enabled through Toll-like receptors (TLRs). TLRs are part of the pattern
recognition receptor (PRR) family, which are molecules vital the innate immune
response and TLR4 is the most studied of the PRR family that specifically
recognizes LPS4. Binding of LPS to the surface of monocytes also
requires the MD-2 protein, which associates with the extracellular domain of
TLR4. An active LPS macromolecular complex is finally formed consisting
of CD14, TLR4 and MD-2 that LPS binds to and initiates an intracellular
signalling cascade ultimately resulting in the transcriptional activation of
genes encoding early NF-?B and related inflammatory cytokines4,5.
This complex triggers the TIRAP–MyD88 pathway which begins with the activation
of My88 adapter where TIRAP acts as a
bridge to recruit MyD88 which in turn, recruits IRAK and TRAF66.
IRAK and TRAF6 form a phosphorylated complex that dissociates from My88 onto
TAK1 and serves as a platform to recruit and activate/phosphorylate the kinase
TAK15. Activated TAK1 activates the IKK complex, which then
phosphorylates I?B, and subsequent degradation of I?B6. . This
allows NF-?B transcription factors (p50/p65) to translocate from the cytoplasm
to the nucleus, and bind to the promoter regions of many pro-in?ammatory
cytokines where it activates multiple gene expression6.