C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NFkB

Sonja I. Gringhuis et al. Immunity 26(5), 605-616 (2007)

Speaker: 黃惠芝                        Place: Room 601

Commentator: 林秋烽 老師              Date: 2007/10/24 14:00-15:00

Abstract:

Dendritic cells (DCs) bridge innate and adaptive immunity and establish protective immunity to pathogens. Pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and C-type lectins can recognize conserved structure of pathogens¹ and transduce signaling that leads to DCs maturation. Previously,  paper showed that the ManLAM of Mycobacteria tuberculosis could bind dendritic cell-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN) to interfere lipopolisaccharides (LPS) induced DCs maturation and increase immunosupressive cytokine interleukin-10 (IL-10) secretion². Therefore the authors planed to study the molecular mechanism underlying the DC-SIGN-TLR crosstalk. The authors stimulated primary human immature DCs with TLR ligands and discovered DC-SIGN signaling not only modulated TLR4 signaling but also TLR3/5. They found that DC-SIGN activated Raf-1 through Ras and phosphorylate/acetylate p65 subunit of NFkB which were phosphorylated at S536 by TLR4 signaling already. Nevertheless, it was not through MEK1/2 pathway. They also found NFkB p65 acetylation and activation of Raf-1 prolonged transcriptional activity of NFkB and enhanced transcription rate from the IL-10 gene. These data reveals that DC-SIGN bind pathogens can modulate TLR signaling via activation of several molecules, and regulate IL-10 secretion that lead to specific adaptive immune response.

References

1. Myeong Sup Lee et al Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic Space. Mol. Cells. 23(1), 1-10 (2007)

2. Geijtenbeek, et al Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7-17 (2003)