Serum Amyloid A Is an Endogenous Ligand That Differentially Induces IL-12 and IL-23

He, Rong; Shepard, Larry W.; Chen, Jia; Pan, Zhixing K.; Ye, Richard D.

doi:10.4049/jimmunol.177.6.4072

Cited by 89 publications

(90 citation statements)

References 66 publications

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“…It is well established that FPRL1 stimulation leads to activation of MAPK signal transduction pathways, 41 which have important roles in regulating collagen production in cardiac fibroblasts and human mesangial cells. 42,43 In this study, we demonstrate that ERK signaling is required for LL-37-induced collagen production in HFL-1 cells.…”

Section: Discussionmentioning

confidence: 99%

LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease

Sun

Zhu

Yang

et al. 2014

Laboratory Investigation

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Emerging evidence suggests that the process of small airway remodeling is mediated by profibrotic growth factors produced by epithelium, which are capable of activating the underlying mesenchymal cells with excessive collagen production. It has been demonstrated that human cathelicidin antimicrobial protein LL-37 is highly expressed in small airway epithelium from COPD patients. However, it is unknown whether the increased levels of LL-37 in epithelium are involved in the pathogenesis of small airway remodeling in COPD. In this study, we examined the expression of LL-37 in small airways from smokers with COPD and controls (non-smokers and smokers without COPD) by immunohistochemistry, and then the association between LL-37 expression in epithelium and the structural changes of small airway remodeling was analyzed. In vitro, the effect of CSE-induced epithelial secretion of LL-37 on collagen production in human lung fibroblasts (HFL-1 cell line) was studied in a co-culture system. Finally, the signaling pathways involved in the effect of LL-37 on fibroblast collagen production were evaluated. The results showed that LL-37 immunoreactivity in airway epithelium was significantly elevated in smokers with COPD compared with controls. In addition, the magnitude of LL-37 expression in epithelium was positively correlated with airway wall thickness and collagen deposition. In vitro, CSE-induced epithelial secretion of LL-37 promoted fibroblast collagen production. Finally, we showed that formyl peptide receptor-like 1 (FPRL1)-dependent extracellular signal-regulated kinase (ERK) signaling pathway was essential for LL-37-induced collagen production in HFL-1 cells. These results suggest that after cigarette smoke exposure, the increased levels of LL-37 in airway epithelium could stimulate collagen production in the underlying lung fibroblasts and may contribute to small airway remodeling in COPD.

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Section: Discussionmentioning

confidence: 99%

LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease

Sun

Zhu

Yang

et al. 2014

Laboratory Investigation

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“…Although several cytokines can promote Th17 expansion [10], we here demonstrate that obesity-associated Th17 expansion is IL-6 dependent. Other cytokines may further amplify this role of IL-6, indeed, serum amyloid A, an acute-phase protein highly elevated in obesity, has been shown to increase dendritic cell IL-23 production in vitro [20].…”

Section: Dio Exacerbates Eaementioning

confidence: 99%

Obesity predisposes to Th17 bias

et al. 2009

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Obesity is associated with numerous inflammatory conditions including atherosclerosis, autoimmune disease and cancer. Although the precise mechanisms are unknown, obesity‐associated rises in TNF‐α, IL‐6 and TGF‐β are believed to contribute. Here we demonstrate that obesity selectively promotes an expansion of the Th17 T‐cell sublineage, a subset with prominent pro‐inflammatory roles. T‐cells from diet‐induced obese mice expand Th17 cell pools and produce progressively more IL‐17 than lean littermates in an IL‐6‐dependent process. The increased Th17 bias was associated with more pronounced autoimmune disease as confirmed in two disease models, EAE and trinitrobenzene sulfonic acid colitis. In both, diet‐induced obese mice developed more severe early disease and histopathology with increased IL‐17+ T‐cell pools in target tissues. The well‐described association of obesity with inflammatory and autoimmune disease is mechanistically linked to a Th17 bias.

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“…In recent studies, several reagents, including whole pathogens, have been found to stimulate DCs to produce IL-23 (30). Serum amyloid A, an acute phase protein, PGE 2 , and phagocytosis of apoptotic neutrophils, each of which are found in inflammatory conditions, have been shown to generate IL-23 production by DCs (31)(32)(33)(34). These stimulators might enhance the constitutive production of CCL19 by DCs, which results in augmentation of IL-23 production in an autocrine manner.…”

Section: Figurementioning

confidence: 99%

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

Kuwabara¹,

Ishikawa²,

Yasuda³

et al. 2009

The Journal of Immunology

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CCL19 and CCL21 are thought to be critical for experimental autoimmune encephalomyelitis (EAE) induction, but their precise role is unknown. We examined the role of these chemokines in inducing EAE. C57BL/6 mice lacking expression of these chemokines (plt/plt mice) or their receptor CCR7 were resistant to EAE induced with myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) and pertussis toxin. However, passive transfer of pathogenic T cells from wild-type mice induced EAE in plt/plt mice, suggesting a defect independent of the role of CCR7 ligands in the migration of immune cells. Examination of draining lymph node (DLN) cells from MOG35–55-immunized plt/plt mice found decreased IL-23 and IL-12 production by plt/plt dendritic cells (DCs) and a concomitant defect in Th17 cell and Th1 cell generation. In contrast, production of the Th17 lineage commitment factors IL-6 and TGF-β were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG35–55-immunized plt/plt mice developed EAE in wild-type recipient mice, whereas that of Th1 cells did not. Pathogenic Th17 cell generation was restored in plt/plt DLNs with the addition of exogenous IL-23 or CCL19/CCL21 and could be reversed by inclusion of anti-IL-23 mAb in cultures. Exogenous CCL19/CCL21 induced IL-23p19 expression and IL-23 production by plt/plt or wild-type DCs. Therefore, CCR7 ligands have a novel function in stimulating DCs to produce IL-23 and are important in the IL-23-dependent generation of pathogenic Th17 cells in EAE induction.

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Serum Amyloid A Is an Endogenous Ligand That Differentially Induces IL-12 and IL-23

Cited by 89 publications

References 66 publications

LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease

LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease

Obesity predisposes to Th17 bias

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

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