Effect of IL-4-regulated DC-SIGN on immune function of dentritic cells and relationship of its expression with tuberculosis / 第三军医大学学报

0.05), but for the DCs with low DC-SIGN expression, the ability was much lower than those of the other group did (P

The Function of Dimeric Structure of Soluble Intercellular Adhesion Molecule - 1 ( sICAM-1 ): Inhibition of Leukocyte Function Associated Antigen - 1 ( LFA-1 ) Binding to ICAM-3

Intercellular adhesion molecule-1 (ICAM-1) is a membrane protein, exists as a dimer on the cell surface, and interacts with leukocyte function associated antigen-1 (LFA-1), a member of beta2-integrin family. A soluble circulating form of ICAM-1 (sICAM-1) is also detected in human serum, and has been implicated as a regulator for LFA-1-dependent cell-cell interaction in vivo. However, previous reports demonstrated that sICAM-1 shows little inhibitory effect on LFA-1 binding to ICAM-l, indicating that sICAM-1 is unlikely to antagonize LFA-1/ICAM-1-mediated cellular events in vivo. Here, we investigated the property of the dimeric sICAM-1 as an inhibitor of LFA-1 interaction with ICAM-3, since the lower avidity of LFA-1 for ICAM-3 compared with ICAM-1 or ICAM-2 had been speculated. Using recently constructed heterodimeric sICAM-1 joined at the C terminus via an a-helical coiled coil (ACID-BASE) (Jun, CD. et al., 2001, Proc Natl Acad Sci 98, 6830-6835), we also tested whether the structural integrity in dimer could affect the inhibitory action of sICAM-1. Engineered sICAM-1 dimer that contained intact ectodomain (E34/E34) significantly blocked SKW3 cell (LFA-1+) binding to ICAM-3, but not to ICAM-1 and ICAM-2, indicating the lower avidity of LFA-1 to ICAM-3 than that of both ICAM-1 and ICAM-2. A one binding site knock out mutant (E34/K34) showed -2-fold reduction in efficiency compared with E34/E34 to inhibit cell binding. Interestingly, a one binding domain deletion mutant (E34/deltaD1-D2) showed significant reduction (~5-fold) compare with E34/K34, suggesting that structural integrity, which is precluded in E34/deltaD1-D2, is necessary for optimal binding of dimeric sICAM-1 to LFA-1, thereby inhibiting LFA-1/ICAM-3-dependent adhesion. Furthermore, BIAcore affinity measurements revealed that E34/deltaD1-D2 bound to immobilized soluble open LFA-1 I domain with an -3-fold reduced affinity compared with E34/K34. Overall, our results demonstrate that maintaining the structural integrity in dimer is necessary for optimal binding of sICAM-1 to LFA-1, and further suggest the therapeutic potential of dimeric sICAM-1 to antagonize LFA-1/ICAM-3-mediated cellular events in vivo.

Expression and regulation of DC-SIGN gene in cutaneous Trichosporon asahii infection in mice / 解放军医学杂志

Objective Dentritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) is an important receptor for pathogenic microbes, and it acts as pathogen-recognition receptor (PAMP) and provides a bridge between the innate immunity and acquired immunity. It is meaningful to clarify whether DC-SIGN takes part in the course of cutaneous Trichosporon asahii infection and how it manages the other cytokines. Methods Twenty-five male mice were hypodermically injected with 3.2?107 CFU/ml of Trichosporon asahii suspension on one side of the back, the other side of the back received no injection to serve as control. Another five mice were treated with 0.9% saline solution as control. The cutaneous specimens were obtained on the 1st, 3rd, 7th and 14th day after inoculation. The expression of DC-SIGN gene and the other genes related to cutaneous immunity after cutaneous infection of Trichosporon asahii were investigated by RT-PCR and microarray. Results The DC-SIGN products containing 242 bp of nucleic acid from the skin specimens of the inoculated sites were amplified with RT-PCR on the 3rd, 7th and 14th day after inoculation. The results of microarray showed that a series of genes were down-regulated, including complement component 2, TNF-inducible protein cg12-1 (CG12-1), interferon-induced protein with tetratricopeptide repeats 3 (Ifit3), CD53 antigen, CD22 antigen, and prostaglandin E receptor 4. Conclusions The results suggest that DC-SIGN takes part in the course of Trichosporon asahii infection. DC-SIGN not only inhibits Th1 type of cell-mediated immunity, but also inhibits some of complement factors, prostaglandin E receptor and immunoglobulin binding protein 1b, thus resulting in chronic and intractable infection of Trichosporon asahii. The detailed roles of DC-SIGN in the course need to be further studied.