Mannose-Binding Lectin Inhibits Monocyte Proliferation through Transforming Growth Factor-β1 and p38 Signaling Pathways

Abstract

Mannose-binding lectin (MBL), a plasma C-type lectin, plays an important role in innate immunity. However, the interaction, and the consequences of it, between MBL and the immune system remain ill defined. We have investigated the contributing mechanisms and effects of MBL on the proliferation of human monocytes. At lower concentrations (≤4 μg/ml) MBL was shown to partially enhance monocyte proliferation. By contrast, at higher concentrations (8–20 μg/ml) of MBL, cell proliferation was markedly attenuated. MBL-induced growth inhibition was associated with G0/G1 arrest, down-regulation of cyclin D1/D3, cyclin-dependent kinase (Cdk) 2/Cdk4 and up-regulation of the Cdk inhibitory protein Cip1/p21. Additionally, MBL induced apoptosis, and did so through caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage. Moreover, transforming growth factor (TGF)-β1 levels increased in the supernatants of MBL-stimulated monocyte cultures. We also found that MBL-dependent inhibition of monocyte proliferation could be reversed by the TGF-β receptor antagonist SB-431542, or by anti-TGF-β1 antibody, or by the mitogen-activated protein kinase (MAPK) inhibitors specific for p38 (SB203580), but not ERK (U0126) or JNK (SP600125). Thus, at high concentrations, MBL can affect the immune system by inhibiting monocyte proliferation, which suggests that MBL may exhibit anti-inflammatory effects.

Mannan‐binding lectin attenuates acetaminophen‐induced hepatotoxicity by regulating CYP2E1 expression via ROS‐dependent JNK/SP1 pathway

“…In the present study, we investigated the signaling pathway and found that the phosphorylations of JNK, ERK and p38 were all significantly increased in MBL –/– mice after APAP treatment, suggesting that MBL attenuates the hepatic activation of MAPKs pathway in the context of APAP overdosing. The result is consistent with our and others’ previous reports showing that MBL could significantly down‐regulate the phosphorylation of MAPKs in different cell types in response to various stimulation . Among the MAPKs, JNK acts as a central player in the pathophysiology of APAP‐induced liver injury .…”

High Expression of Mannose-Binding Lectin and the Risk of Vascular Complications of Diabetes: Evidence from a Meta-Analysis

“…As described in detail previously, 6 high concentrations of MBL in type 2 diabetes patients might participate in the down-regulation of proliferation and function in monocytes. It implied that high MBL expression in serum might play a negative regulatory role in the chronic inflammation mediated by monocytes.…”

“…It implied that high MBL expression in serum might play a negative regulatory role in the chronic inflammation mediated by monocytes. 6 It might be similar to the effect of pentraxin 3 in myocardial infarction. 25 Thus, we presume further investigations with large sample sizes are still needed that could provide evidence of the effect of high concentrations of MBL in serum on immune regulation in peripheral, local, and even extravascular tissues during inflammation.…”

“…According to our previous study, which was described in detail elsewhere, 6 and other evidence, overzealous responses of the complement system may lead to the development of vascular complications in diabetes. 1,6 Three different pathways, named the mannose-binding lectin (MBL), the classical, and the alternative pathways, can activated the complement system. MBL is the major recognition and initiation molecule of the lectin pathway of complement activation.…”

Mannan‐binding lectin at supraphysiological concentrations inhibits differentiation of dendritic cells from human CD14+ monocytes

“…A similar phenomenon has been observed when IL‐10 was added at the initiation of culture , which possibly explains the mechanism by which MBL affects differentiation (as discussed below). Our group has previously documented the arrest of monocytes in the G0/G1 phase of a cell cycle by MBL treatment . Cell apoptosis was one of the effects of the interaction between monocytes and MBL in that study.…”