Biology Reference
In-Depth Information
Triantifilou and colleagues have reported that LPS was able to bind
several proteins like the heat shock proteins Hsp70 and Hsp90,
chemokine receptor 4, and growth differentiation factor 5 (Triantafilou
et al.
, 2001, Triantafilou and Triantafilou, 2002). Recent reviews that
have focused on LPS/lipid A receptor molecules can be consulted for
further details (Dauphinee and Karsan, 2006, Amersfoort
et al.
, 2003).
After LPS interacts with the TLR4/MD-2 complex, several
intracellular signaling pathways are activated. The cytoplasmic portion
of TLR4 belongs to a signaling domain family called the Toll-
interleukin-1 receptor (TIR) domain, which is shared by all TLRs and the
IL-1 receptor family. Activation of TLR4 by LPS leads to dimerization
of the TIR and recruitment of TIR adaptor proteins (TIRAP) such as
myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like protein
(Mal or TIRAP), TIR-containing adaptor inducing IFNβ (TRIF, TIRAP-
1, or TICAM-1), and TRIF-related adaptor molecule (TRAM, TIRAP-2,
or TICAM-2) to enhance signaling. The TIR serves as a dock for these
adaptor proteins. Then, one or both of two pathways are activated: the
MyD88-dependent pathway and the MyD88-independent pathway. The
MyD88-dependent pathway acts through a series of two different
cascade signaling channels involving several mediator proteins, starting
with MyD88, which leads to the independent activation of c-Jun N-
terminal kinase (JNK) and degradation of the inhibitor of NF-κB (iκB).
JNK is a mitogen-activated protein kinase (MAPK). Activation of JNK
and degradation of iκB results in the release of several inflammatory
cytokines including TNFα, IL-1, and IL-6 through the activation of two
transcription factors, activator protein-1 (AP-1) and NF-κB, respectively.
Also produced are monocyte chemoattractant protein 1 (MCP-1),
macrophage inflammatory protein 3α (MIP-3α), IL-8, and
cyclooxygenase 2 (COX-2). The MyD88-independent pathway, which
was discovered with MyD88 knockout mice, after a series of events,
ends in the activation of interferon regulatory factor 3 (IRF3, a
transcription factor) and eventually the production of INF-β. Released
INF-β can then influence the production of antimicrobial agents such as
type 1 INF-α/β, INFα inducible protein-10 (IP-10), monocyte
chemoattractant protein-5 (MCP-5), RANTES, and nitric oxide (Kawai
et al.
, 2001, Zughaier
et al.
, 2005). In the MyD88-independent pathway,
