MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4

Abstract

Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila Toll, a leucine-rich repeat molecule that can trigger innate responses against pathogens. The TLR4 gene has recently been shown to be mutated in C3H/HeJ and C57BL/10ScCr mice, both of which are low responders to lipopolysaccharide (LPS). TLR4 may be a long-sought receptor for LPS. However, transfection of TLR4 does not confer LPS responsiveness on a recipient cell line, suggesting a requirement for an additional molecule. Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. MD-2 is thus a link between TLR4 and LPS signaling. Identification of this new receptor complex has potential implications for understanding host defense, as well as pathophysiologic, mechanisms.

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

“…In myeloid cells, the LPS/LPS-binding protein complex binds CD14 and MD-2 [4,5] and the subsequent dimerisation of TLR4 recruits IL-1R-associated serine kinase-4 (IRAK-4) via the adaptors myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor protein (TIRAP) [29,30]. As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32].…”

“…Lipolysaccharide (LPS), flagellin, peptidoglycan or DNA may bind directly to the TLR but in addition, co-receptors are needed to enhance the TLR response to these conserved ligands [1][2][3]. Myeloid cells use CD14 and MD-2 as co-receptors for LPS in TLR4 signalling, and minute amounts of LPS may elicit a strong systemic inflammatory response [4,5]. However, the TLR response to pathogen attack at mucosal surfaces is controlled by different interactions.…”

“…1). The results showed that P fimbriated E. coli trigger a TLR4-dependent response in vivo in the urinary tract and that the urinary tract mucosa remains inert when exposed to a non-adhesive strain, or when TLR4 is inactivated.Involvement of Trif Lps2/Lps2 /Tram in the response to P fimbriated E. coliIn myeloid cells, the LPS/LPS-binding protein complex binds 5] and the subsequent dimerisation of TLR4 recruits IL-1R-associated serine kinase-4 (IRAK-4) via the adaptors myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor protein (TIRAP) [29,30]. As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32].…”

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

“…These observations indicate that specific events that occur upstream of Raf-1 signalling are responsible for these differences. In fact, the assembly and activation of the receptors could account for the differential time-courses; c-fms receptor requires non-covalent dimerization and autophosphorylation of tyrosine kinase domains [49], while recognition of LPS requires the assembly of TLR4 with CD14, LPS-binding protein and MD-2 [50,51].…”

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

“…The Irish CD group comprised 113 patients (77 females and 36 males) with a median age at diagnosis of 27.5 years (IQR [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. This corresponded to 38 patients diagnosed before the age of 40 years (A1) and 21 diagnosed after the age of 40 years (A2).…”