TY - JOUR
T1 - Lipocalin 2 is a regulator of macrophage polarization and NF-κB/STAT3 pathway activation
AU - Guo, Hong
AU - Jin, Daozhong
AU - Chen, Xiaoli
N1 - Publisher Copyright:
© 2014 by the Endocrine Society. All rights reserved.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Lipocalin 2 (Lcn2) has been previously characterized as an adipokine/cytokine and implicated in obesity and inflammation. Herein, we investigated the role and potential mechanism of Lcn2 in the regulation of macrophage polarization in obesity-associated inflammation. We observed that Lcn2-/- mice displayed an up-regulation of expression of M1 macrophage marker Cd11c but a down-regulation of M2 marker arginase 1 in adipose tissue and liver of mice upon a high-fat diet feeding. Lcn2-deficient bone marrow–derived macrophages (BMDMs) were more sensitive to lipopolysaccharide (LPS) stimulation, leading to a more profound up-regulation of expression of pro-inflammatory markers than wild-type (WT) BMDMs. Accordingly, LPS stimulation elicited an increase in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun, and STAT3 signaling pathways as well as an up-regualtion of expression of NF-κB and STAT3 target genes such as IL-1β, IL-6, iNOS, and MCP-1 in Lcn2-/- BMDMs compared with WT controls. Pre-treatment of recombinant Lcn2 attenuated LPS-stimulated degradation of IκBα and STAT3 phosphorylation as well as LPS-induced gene expression of IL-6 and iNOS in Lcn2-/- BMDMs. Moreover, the NFκB inhibitor markedly blocked LPS-stimulated STAT3 phosphorylation in Lcn2-/- BMDMs. These results together with the time course of Lcn2 secretion, NFκB and STAT3 phosphorylation in response to LPS stimulation, suggest that Lcn2 plays a role as an anti-inflammatory regulator in macrophage activation via modulating a feed-forward activation of NFκBSTAT3 loop.
AB - Lipocalin 2 (Lcn2) has been previously characterized as an adipokine/cytokine and implicated in obesity and inflammation. Herein, we investigated the role and potential mechanism of Lcn2 in the regulation of macrophage polarization in obesity-associated inflammation. We observed that Lcn2-/- mice displayed an up-regulation of expression of M1 macrophage marker Cd11c but a down-regulation of M2 marker arginase 1 in adipose tissue and liver of mice upon a high-fat diet feeding. Lcn2-deficient bone marrow–derived macrophages (BMDMs) were more sensitive to lipopolysaccharide (LPS) stimulation, leading to a more profound up-regulation of expression of pro-inflammatory markers than wild-type (WT) BMDMs. Accordingly, LPS stimulation elicited an increase in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun, and STAT3 signaling pathways as well as an up-regualtion of expression of NF-κB and STAT3 target genes such as IL-1β, IL-6, iNOS, and MCP-1 in Lcn2-/- BMDMs compared with WT controls. Pre-treatment of recombinant Lcn2 attenuated LPS-stimulated degradation of IκBα and STAT3 phosphorylation as well as LPS-induced gene expression of IL-6 and iNOS in Lcn2-/- BMDMs. Moreover, the NFκB inhibitor markedly blocked LPS-stimulated STAT3 phosphorylation in Lcn2-/- BMDMs. These results together with the time course of Lcn2 secretion, NFκB and STAT3 phosphorylation in response to LPS stimulation, suggest that Lcn2 plays a role as an anti-inflammatory regulator in macrophage activation via modulating a feed-forward activation of NFκBSTAT3 loop.
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U2 - 10.1210/me.2014-1092
DO - 10.1210/me.2014-1092
M3 - Article
C2 - 25127375
AN - SCOPUS:84907618625
SN - 0888-8809
VL - 28
SP - 1616
EP - 1628
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 10
ER -