Wnt5a stimulates chemotactic migration and chemokine production in human neutrophils

Wnt5a is a ligand that activates the noncanonical Wnt signaling pathways (beta-catenin-independent pathways). Human neutrophils expressed several Wnt5a receptors, such as Frizzled 2, 5 and 8. Stimulation of human neutrophils with Wnt5a caused chemotactic migration and the production of two important chemokines, CXCL8 and CCL2. CCL2 production by Wnt5a was mediated by a pertussis toxin-sensitive G-protein-dependent pathway. Wnt5a also stimulated the phosphorylation of three mitogen-activated protein kinases (MAPKs: ERK, p38 MAPK and JNK) and Akt. Inhibition of ERK, p38 MAPK or JNK by specific inhibitors induced a dramatic reduction in Wnt5a-induced CCL2 production. Supernatant collected from lipopolysaccharide-stimulated macrophages induced neutrophil chemotaxis, which was significantly inhibited by anti-Wnt5a antibody. Our results suggested that Wnt5a may contribute to neutrophil recruitment, mediating the inflammation response.

The immune-stimulating peptide WKYMVm has therapeutic effects against ulcerative colitis

In this study, we examined the therapeutic effects of an immune-stimulating peptide, WKYMVm, in ulcerative colitis. The administration of WKYMVm to dextran sodium sulfate (DSS)-treated mice reversed decreases in body weight, bleeding score and stool score in addition to reversing DSS-induced mucosa destruction and shortened colon. The WKYMVm-induced therapeutic effect against ulcerative colitis was strongly inhibited by a formyl peptide receptor (FPR) 2 antagonist, WRWWWW, indicating the crucial role of FPR2 in this effect. Mechanistically, WKYMVm effectively decreases intestinal permeability by stimulating colon epithelial cell proliferation. WKYMVm also strongly decreases interleukin-23 and transforming growth factor-beta production in the colon of DSS-treated mice. We suggest that the potent immune-modulating peptide WKYMVm and its receptor FPR2 may be useful in the development of efficient therapeutic agents against chronic intestinal inflammatory diseases.

Identification of novel peptides that stimulate human neutrophils

Neutrophils play a key role in innate immunity, and the identification of new stimuli that stimulate neutrophil activity is a very important issue. In this study, we identified three novel peptides by screening a synthetic hexapeptide combinatorial library. The identified peptides GMMWAI, MMHWAM, and MMHWFM caused an increase in intracellular Ca2+ in a concentration-dependent manner via phospholipase C activity in human neutrophils. The three peptides acted specifically on neutrophils and monocytes and not on other non-leukocytic cells. As a physiological characteristic of the peptides, we observed that the three peptides induced chemotactic migration of neutrophils as well as stimulated superoxide anion production. Studying receptor specificity, we observed that two of the peptides (GMMWAI and MMHWFM) acted on formyl peptide receptor (FPR)1 while the other peptide (MMHWAM) acted on FPR2. Since the three novel peptides were specific agonists for FPR1 or FPR2, they might be useful tools to study FPR1- or FPR2-mediated immune response and signaling.

A pertussis toxin sensitive G-protein-independent pathway is involved in serum amyloid A-induced formyl peptide receptor 2-mediated CCL2 production

Serum amyloid A (SAA) induced CCL2 production via a pertussis toxin (PTX)-insensitive pathway in human umbilical vein endothelial cells (HUVECs). SAA induced the activation of three MAPKs (ERK, p38 MAPK, and JNK), which were completely inhibited by knock-down of formyl peptide receptor 2 (FPR2). Inhibition of p38 MAPK and JNK by their specific inhibitors (SB203580 and SP600125), or inhibition by a dominant negative mutant of p38 MAPK dramatically decreased SAA-induced CCL2 production. Inactivation of Gi protein(s) by PTX inhibited the activation of SAA-induced ERK, but not p38 MAPK or JNK. The results indicate that SAA stimulates FPR2-mediated activation of p38 MAPK and JNK, which are independent of a PTX-sensitive G-protein and are essential for SAA-induced CCL2 production.

Lysophosphatidylglycerol inhibits formyl peptide receptor like-1-stimulated chemotactic migration and IL-1beta production from human phagocytes

In this study, we observed that lysophosphatidylglycerol (LPG) completely inhibited a formyl peptide receptor like-1 (FPRL1) agonist (MMK-1)-stimulated chemotactic migration in human phagocytes, such as neutrophils and monocytes. LPG also dramatically inhibited IL-1beta production by another FPRL1 agonist serum amyloid A (SAA) in human phagocytes. However, LPG itself induced intracellular calcium increase and superoxide anion production in human phagocytes. Keeping in mind that phagocytes migration and IL-1beta production by FPRL1 are important for the induction of inflammatory response, our data suggest that LPG can be regarded as a useful material for the modulation of inflammatory response induced by FPRL1 activation.

LL-37 inhibits serum amyloid A-induced IL-8 production in human neutrophils

Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.

LL-37 inhibits serum amyloid A-induced IL-8 production in human neutrophils

Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.

The relationship between the morphology of mandibular symphysis and the craniofacial morphology in class lll malocclusion / 대한치과교정학회지

By studying the relationship between the morphology of mandibular symphysis and craniofacial morphology in class III malocclusion, this study aims at deciding whether the morphogy of mandibular symphysis can be used as a predictor on the growth of mandible. The materials used for this study were the cephalometric radiographs of male class III malocclusion. The subjected age groups were 10-12(G1 group) and 20 and above(G2 group); 50 were selected from each group. Each group was again divided, according to the ratio of symphysis, into Large(L), Average(A), and Small(S). The results of this study were summarized as follows: 1. In average the ratio of symphysis, G2 group showed significantly bigger than G1 group(P0.05). 3. In both G1 and G2 groups, there was not distinct difference in the antero-posterior positions among L, A, S subgroups. 4. L and A subgroups showed significantly larger than S subgroup in lower gonial angle and chin angle in G1 group (P<0.05) 5. In the measurements on the vertical relation of the face, anterior total face height(ATFH) and anterior lower face height(ALFH) of L subgroup were significantly larger than that of S subgroup in G1 group(P<0.05) and also mandible showed a tendency to grow downward vertically. 6. In the measurements on the tooth position and inclination, L subgroup showed as compared with S subgroup a tendency of extrusion of maxillary and mandibular teeth in G1 group, but G2 group showed such tendency only in mandibular teeth. 7. In the measurements on the abnormal growth prediction by Schulhof, in G1, there was no significant difference among L, A, S sugroups. 8. In the correlative analysis of the ratio of symphysis and other measurements, G1 group showed significant correlationships in chin angle, PP/MP angle, ANS-Me and other, while G2 group showed the same only in MP-LIT and MP-LMMC(P<0.05, P<0.01). In summarizing the above, in the G1 group, consisting of young males, no difference was noted in horizontal relation between L and S subgroups; in vertical relation, L subgroup showed a stronger tendency of downward growth of mandible than S subgroup. In adult male G2 group, however, no distinct morphological difference of craniofacial complex by the ratio of symphysis.

The relationship between the morphology of mandibular symphysis and the craniofacial morphology in Class III malocclusion / 대한치과교정학회지

By studying the relationship between the morphology of mandibular symphysis and craniofacial morphology in class III malocclusion, this study aims at deciding whether the morphogy of mandibular symphysis can be used as a predictor on the growth of mandible. The materials used for this study were the cephalometric radiographs of male class III malocclusion. The subjected age groups were 10-12(G1 group) and 20 and above(G2 group); 50 were selected from each group. Each group was again divided, according to the ratio of symphysis, into Large(L), Average(A), and Small(S). The results of this study were summarized as follows: 1. In average the ratio of symphysis, G2 group showed significantly bigger than G1 group(P0.05). 3. In both G1 and G2 groups, there was not distinct difference in the antero-posterior positions among L, A, S subgroups. 4. L and A subgroups showed significantly larger than S subgroup in lower gonial angle and chin angle in G1 group (P<0.05) 5. In the measurements on the vertical relation of the face, anterior total face height(ATFH) and anterior lower face height(ALFH) of L subgroup were significantly larger than that of S subgroup in G1 group(P<0.05) and also mandible showed a tendency to grow downward vertically. 6. In the measurements on the tooth position and inclination, L subgroup showed as compared with S subgroup a tendency of extrusion of maxillary and mandibular teeth in G1 group, but G2 group showed such tendency only in mandibular teeth. 7. In the measurements on the abnormal growth prediction by Schulhof, in G1, there was no significant difference among L, A, S sugroups. 8. In the correlative analysis of the ratio of symphysis and other measurements, G1 group showed significant correlationships in chin angle, PP/MP angle, ANS-Me and other, while G2 group showed the same only in MP-LIT and MP-LMMC(P<0.05, P<0.01). In summarizing the above, in the G1 group, consisting of young males, no difference was noted in horizontal relation between L and S subgroups; in vertical relation, L subgroup showed a stronger tendency of downward growth of mandible than S subgroup. In adult male G2 group, however, no distinct morphological difference of craniofacial complex by the ratio of symphysis.