Doxycycline up-regulates the expression of IL-6 and GM-CSF via MAPK/ERK and NF-κB pathways in mouse thymic epithelial cells

Huang, Ying; Li, Rong; Chen, Xun; Zhuo, Ya; Jin, Rong; Qian, Xiao Ping; Jiang, Yan; Zeng, Zhi; Shao, Qixiang

doi:10.1016/j.intimp.2011.03.011

Cited by 11 publications

(8 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NF-κB is a key regulator of the transcription of many inflammatory cytokines [30] . NF-κB translocation into the nucleus is preceded by the phosphorylation of IκBα, a protein that normally sequesters the NF-κB complex in the cytosol in an inactive form.…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB translocation into the nucleus is preceded by the phosphorylation of IκBα, a protein that normally sequesters the NF-κB complex in the cytosol in an inactive form. Following inflammatory stimuli, phosphorylation and degradation of IκBα allow the NF-κB heterodimer to rapidly move into the nucleus [30] , [31] . MAPKs are important factors of inflammatory and stress-induced signal pathways which regulated cell survival and death.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways

Sun

Shigemi

Tanaka

et al. 2015

Biochemistry and Biophysics Reports

View full text Add to dashboard Cite

Recent reports have shown that antibiotics such as macrolide, aminoglycoside, and tetracyclines have immunomodulatory effects in addition to essential antibiotic effects. These agents may have important effects on the regulation of cytokine and chemokine production. However, the precise mechanism is unknown. This time, we used Multi Plex to measure the production of cytokines and chemokines following tetracycline treatment of lipopolysaccharide (LPS)-induced THP-1 cells. The signaling pathways were investigated with Western blotting analysis. Three tetracyclines significantly suppressed the expression of cytokines and chemokines induced by LPS. Minocycline (50 μg/ml), tigecycline (50 μg/ml), or doxycycline (50 μg/ml) were added after treatment with LPS (10 μg/ml). Tumor necrosis factor-α was downregulated to 16%, 14%, and 8%, respectively, after 60 min compared to treatment with LPS without agents. Interleukin-8 was downregulated to 43%, 32%, and 26% at 60 min. Macrophage inflammatory protein (MIP)-1α was downregulated to 23%, 33%, and 16% at 120 min. MIP-1β was downregulated to 21%, 11%, and 2% at 120 min. Concerning about signaling pathways, the mechanisms of the three tetracyclines might not be the same. Although the three tetracyclines showed some differences in the time course, tetracyclines modulated phosphorylation of the NF-κB pathway, p38 and ERK1/2/MAPK pathways, resulting in inhibition of cytokine and chemokine production. In addition, SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor) significantly suppressed the expression of TNF-α and IL-8 in LPS-stimulated THP-1 cells. And further, the NF-κB inhibitor, BAY11-7082, almost completely suppressed LPS-induced these two cytokines production. Thus, more than one signaling pathway may be involved in tetracyclines downregulation of the expression of LPS-induced cytokines and chemokines in THP-1 cells. And among the three signaling pathways, NF-κB pathway might be the dominant pathway on tetracyclines modification the LPS-induced cytokines production in THP-1 cells. In general, minocycline and doxycycline suppressed the production of cytokines and chemokines in LPS-stimulated THP-1 cell lines via mainly the inhibition of phosphorylation of NF-κB pathways. Tigecycline has the same structure as the other tetracyclines, however, it showed the different properties of cytokine modulation in the experimental time course.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways

Sun

Shigemi

Tanaka

et al. 2015

Biochemistry and Biophysics Reports

View full text Add to dashboard Cite

show abstract

“…Our preliminary data show that Dox can drive proliferation in part via the Ras-MAPK signaling pathway [11] and also up-regulate expression of IL-6 and GM-CSF through the MAPK/ERK and NF-κB pathways [12]. Cellular apoptosis is the most prominent feature of thymic involution.…”

Section: Introductionmentioning

confidence: 79%

Doxycycline Protects Thymic Epithelial Cells from Mitomycin C-Mediated Apoptosis In Vitro via Trx2-NF-κB-Bcl-2/Bax Axis

Wang¹,

Zhuo²,

Yin³

et al. 2016

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background/Aims: Age-associated and stress-induced involution of the thymus is accompanied by reduced numbers of thymic epithelial cells (TECs) and severe reduction in peripheral T cell repertoire specificities. These events seriously affect immune function, but the mechanisms involved are unclear. Our preliminary findings showed that doxycycline (Dox) could drive the proliferation of a TEC line (MTEC1 cells) partially via the MAPK signaling pathway. Dox can also up-regulate IL-6 and GM-CSF expression via the NF-κB and MAPK/ERK pathways. Herein, we investigate the effects and mechanisms used by Dox that protect against mitomycin C (MMC)-induced MTEC1 cell apoptosis. Methods: MTEC1 cells were treated with Dox, MMC, and Dox plus MMC for different amounts of time. The expression of Trx2, NF-κB, Bcl-2, and Bax proteins were then detected by western blotting. Results: Our findings show that Dox protects MTEC1 cells from MMC-induced apoptosis. Dox up-regulated the expression of Trx2 and promoted NF-κB phosphorylation. Meanwhile, Dox also increased the expression of Bcl-2, partially reduced the expression of Bax, and normalized the ratio of Bcl-2 to Bax. Conclusion: Dox exerts an anti-apoptosis function via the NF-κB-Bcl-2/Bax and Trx2-ASK1/JNK pathways in vitro. Therefore, Dox may represent a drug that could be used to attenuate thymic senescence, rescue thymic function, and promote T cell reconstitution.

show abstract

“…In contrast, pro-inflammatory effects have been described for doxycycline in murine thymic epithelial cells. Treatment with doxycycline increased the expression of IL-6 and GM-CSF through activation of NFκB and ERK indicating direct pro-inflammatory effects during homeostasis64. Additionally, recent epidemiological studies have shown doxycycline to be associated with CD (odds ratio 2.25)15.…”

Section: Discussionmentioning

confidence: 97%

Doxycycline, metronidazole and isotretinoin: Do they modify microRNA/mRNA expression profiles and function in murine T-cells?

Becker

Bengs

Aluri³

et al. 2016

Sci Rep

View full text Add to dashboard Cite

1Inflammatory bowel disease (IBD) may develop due to an inflammatory response to commensal gut microbiota triggered by environmental factors in a genetically susceptible host. Isotretinoin (acne therapy) has been inconsistently associated with IBD onset and flares but prior treatment with antibiotics, also associated with IBD development, complicates the confirmation of this association. Here we studied in mice whether doxycycline, metronidazole or isotretinoin induce epigenetic modifications, and consequently change T-cell mRNA expression and/or function directly after treatment and after a 4 week recovery period. Isotretinoin induced IL-10 signaling in Tregs and naive T-cells directly after treatment and reduced effector T-cell proliferation alone and in co-culture with Tregs. Metronidazole activated processes associated with anti-inflammatory pathways in both T-cell subsets directly after the treatment period whereas doxycycline induced an immediate proinflammatory expression profile that resolved after the recovery period. Long-term changes indicated an inhibition of proliferation by doxycycline and induction of beneficial immune and metabolic pathways by metronidazole. Persistent alterations in microRNA and mRNA expression profiles after the recovery period indicate that all three medications may induce long-term epigenetic modifications in both T-cell subsets. Yet, our data do not support the induction of a long-term pro-inflammatory phenotype in murine Tregs and naive T-cells.Inflammatory bowel diseases (IBD) with the two main forms, Crohn's disease (CD) and ulcerative colitis (UC), are chronic and relapsing inflammatory conditions of the gastrointestinal tract that affect an increasing number of patients worldwide 1 . The precise pathogenesis of IBD is multifactorial and is not completely elucidated yet. It is generally considered that environmental factors represent an important contributor to the pathogenesis of IBD by triggering an inappropriate and progressive immune response to the commensal gut microbiota in a genetically predisposed host 2 . To date, genome-wide association studies have identified more than 240 IBD susceptibility loci, affecting genes involved in immune regulation, mucosal immune response, autophagy and epithelial barrier function [3][4][5] . Currently available data support the concept that IBD is a polygenic disease and suggest that non-genetic modifications involved in regulatory processes might have an impact on susceptibility and severity of disease 6 . Mechanisms of gene regulation that do not alter the basic sequence of DNA are called epigenetic regulations and have been studied extensively over the last few years. These studies have shown that epigenetic modifications are associated with a variety of diseases, e.g. IBD 7,8 , multiple sclerosis 9 , psoriasis 10 and systemic lupus erythematosus 11. The molecular basis of epigenetic regulation is complex. Importantly, changes may remain through cell division, and last for many generations (long-term effects) 12 . So far, th...

show abstract

Doxycycline up-regulates the expression of IL-6 and GM-CSF via MAPK/ERK and NF-κB pathways in mouse thymic epithelial cells

Cited by 11 publications

References 56 publications

Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways

Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways

Doxycycline Protects Thymic Epithelial Cells from Mitomycin C-Mediated Apoptosis In Vitro via Trx2-NF-κB-Bcl-2/Bax Axis

Doxycycline, metronidazole and isotretinoin: Do they modify microRNA/mRNA expression profiles and function in murine T-cells?

Contact Info

Product

Resources

About