Youl-Nam Lee

Serum Amyloid A Induces Contrary Immune Responses via Formyl Peptide Receptor-Like 1 in Human Monocytes

Although the level of serum amyloid A has been reported to be up-regulated during inflammatory response, the role of serum amyloid A on the regulation of inflammation and immune response has not been elucidated. We found that serum amyloid A stimulated the production of tumor necrosis factor (TNF)-α and interleukin (IL)-10, which are proinflammatory and anti-inflammatory cytokines, respectively, in human monocytes. Low concentrations of serum amyloid A stimulated TNF-α production with maximal activity at 6 h after stimulation, whereas high concentrations of serum amyloid A stimulated IL-10 production with maximal activity at 12 h. The activations of the two cytokines by serum amyloid A occurred at both the transcription and translational levels. Signaling events induced by serum amyloid A included the activation of two mitogen-activated protein kinases (extracellular signal-regulated kinase and p38 kinase), which were found to be required for TNF-α and IL-10 production, respectively. The stimulation of formyl peptide receptor-like-1-expressing RBL-2H3 cells, but not of vector-expressing RBL-2H3 cells with serum amyloid A, induced mitogen-activated protein kinases activation and the accumulation of the RNAs of these two cytokines. Together, our findings suggest that serum amyloid A modulates contrary immune responses via formyl peptide receptor-like 1, by inducing TNF-α or IL-10, and demonstrate that extracellular signal-regulated kinase and p38 kinase play counteracting roles in this process.

Group IB Secretory Phospholipase A2 Stimulates CXC Chemokine Ligand 8 Production via ERK and NF-κB in Human Neutrophils

Although the level of group IB secretory phospholipase A2 (sPLA2-IB) has been reported to be up-regulated during inflammatory response, the role of sPLA2-IB on the regulation of inflammation and immune responses has not been fully elucidated. In this study, we found that sPLA2-IB stimulates the expression and secretion of CXCL8 without affecting other proinflammatory cytokines, such as IL-1β or TNF α in human neutrophils. The induction of CXCL8 secretion by sPLA2-IB occurs at both the transcription and translational levels and correlates with activation of NF-κB. Moreover, the NF-κB inhibitors pyrrolidinedithiocarbamate, dexamethasone, or sulfasalazine were found to prevent CXCL8 production by sPLA2-IB in human neutrophils. In addition, the signaling events induced by sPLA2-IB included activation of the MAPK ERK and an increase in intracellular Ca2+, which are both required for CXCL8 production. The exogenous addition of sPLA2-IB did not induce arachidonic acid release from human neutrophils, and the inactivation of sPLA2-IB by EGTA did not affect CXCL8 production by sPLA2-IB in human neutrophils. Taken together, we suggest that sPLA2-IB plays a role in the modulation of inflammatory and immune responses via the sPLA2 receptor, by inducing CXCL8 in human neutrophils.

Trp-Lys-Tyr-Met-Val-Met stimulates phagocytosis via phospho-lipase D-dependent signaling in mouse dendritic cells.

Dendritic cells (DCs) play a key role in activating the immune response against invading pathogens as well as dying cells or tumors. Although the immune response can be initiated by the phagocytic activity by DCs, the molecular mechanism involved in this process has not been fully investigated. Trp-Lys-Tyr-Met-Val-Met-NH2 (WKYMVM) stimulates the activation of phospholipase D (PLD) via Ca2+ increase and protein kinase C activation in mouse DC cell line, DC2.4. WKYMVM stimulates the phagocytic activity, which is inhibited in the presence of N-butanol but not t-butanol in DC2.4 cells. Furthermore, the addition of phosphatidic acid, an enzymatic product of PLD activity, enhanced the phagocytic activity in DC2.4 cells. Since at least two of formyl peptide receptor (FPR) family (FPR1 and FPR2) are expressed in DC2.4 as well as in mouse bone marrow-derived dendritic cells, this study suggests that the activation of FPR family by WKYMVM stimulates the PLD activity resulting in phagocytic activity in DC2.4 cells.