Palmitate Activates CCL4 Expression in Human Monocytic Cells via TLR4/MyD88 Dependent Activation of NF-κB/MAPK/ PI3K Signaling Systems

Autor: Betty Chandy, Ajit Wilson, Jaakko Tuomilehto, Steve Shenouda, Rasheed Ahmad, Sardar Sindhu, Shihab Kochumon
Rok vydání: 2017
Předmět:
0301 basic medicine
MAPK/ERK pathway
Lipopolysaccharides
Chemokine
Physiology
Palmitates
Adipose tissue
Palmitate
lcsh:Physiology
Wortmannin
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
lcsh:QD415-436
TLR4
Phosphorylation
RNA
Small Interfering
Chemokine CCL4
Cells
Cultured
Phosphoinositide-3 Kinase Inhibitors
Leukemia
lcsh:QP1-981
biology
NF-kappa B
Cell Differentiation
Cell biology
Up-Regulation
CCL4/MIP-1beta
RNA Interference
Signal transduction
medicine.symptom
Mitogen-Activated Protein Kinases
Signal Transduction
Morpholines
CCL4
Inflammation
digestive system
lcsh:Biochemistry
03 medical and health sciences
medicine
Humans
Antibodies
Neutralizing
Toll-Like Receptor 4
Transcription Factor AP-1
030104 developmental biology
chemistry
Cell culture
Chromones
Myeloid Differentiation Factor 88
biology.protein
Leukocytes
Mononuclear
Zdroj: Cellular Physiology and Biochemistry, Vol 46, Iss 3, Pp 953-964 (2018)
ISSN: 1421-9778
Popis: Background/Aims: Obesity is associated with adipose tissue inflammation which plays a key role in the development of insulin resistance and type 2 diabetes (T2D). Saturated free fatty acids (SFAs) levels are found to be elevated in obesity and T2D. Chemokines are known to have potent inflammatory functions in a wide range of biological processes linked to immunological disorders. Since CCL4 (Chemokine (C-C motif) ligand 4), also known as macrophage inflammatory protein-1β (MIP-1β), plays an important role in the migration of monocytes into the adipose tissue, we investigated the expression of CCL4 in monocytic cells/macrophages following activation with free fatty acid palmitate. Methods: Human monocytic cell line THP-1 and macrophages derived from THP-1 and primary monocytes were stimulated with palmitate and LPS (positive control). CCL4 expression and secretion were measured with real time RT-PCR and ELISA respectively. Signaling pathways were identified by using THP-1-XBlueTM cells, THP-1-XBlueTM-defMyD cells, anti-TLR4 mAb and TLR4 siRNA. Results: Palmitate induces CCL4 expression at both mRNA and protein levels in human monocytic cells. Palmitate-induced CCL4 production was markedly suppressed by neutralizing anti-TLR-4 antibody. Additionally, silencing of TLR4 by siRNA also significantly suppressed the palmitate-induced up-regulation of CCL4. MyD88-deficient cells did not express CCL4 in response to palmitate treatment. Inhibition of NF-kB and MAPK pathways suppressed the palmitate mediated induction of CCL4. Moreover, induction of CCL4 was blocked by PI3 Kinase inhibitors LY294002 and wortmannin. Conclusion: Collectively, our results show that palmitate induces CCL4 expression via activation of the TLR4-MyD88/NF-kB/MAPK/ PI3K signaling cascade. Thus, our findings suggest that the palmitate-induced CCL4 production might be an underlying mechanism of metabolic inflammation.
Databáze: OpenAIRE
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