Quercetagetin inhibits macrophage-derived chemokine in HaCaT human keratinocytes via the regulation of signal transducer and activator of transcription 1, suppressor of cytokine signalling 1 and transforming growth factor-β1.

Abstract

BACKGROUND:

Inflammatory chemokines, such as macrophage-derived chemokine (MDC/CCL22), are elevated in the serum and lesioned skin of patients with atopic dermatitis (AD), and are ligands for C-C chemokine receptor 4, which is predominantly expressed on T helper 2 lymphocytes, basophils and natural killer cells. We have previously reported that quercetagetin has an inhibitory activity on inflammatory chemokines, which is induced by interferon (IFN)-γ and tumour necrosis factor (TNF)-α, occurring via inhibition of the signal transducer and activator of transcription 1 (STAT1) signal.

OBJECTIVES:

To investigate the specific mechanisms of quercetagetin on the STAT1 signal.

METHODS:

We confirmed the inhibitory activity of quercetagetin on MDC and STAT1 in HaCaT keratinocytes. The interaction between STAT1 and IFN-γR1 was investigated using immunoprecipitation. The small interfering RNA approach was used to investigate the role of suppressor of cytokine signalling 1 (SOCS1) and transforming growth factor (TGF)-β1 induced by quercetagetin.

RESULTS:

Quercetagetin inhibited the expression of MDC at both the protein and mRNA levels in IFN-γ- and TNF-α-stimulated HaCaT human keratinocytes. Moreover, quercetagetin inhibited the phosphorylation of STAT1 through upregulation of SOCS1. Increased expression of SOCS1 disrupted the binding of STAT1 to IFN-γR1. Furthermore, quercetagetin augmented the expression of TGF-β1, which is known to modulate the immune response and inflammation.

CONCLUSIONS:

These results suggest that quercetagetin may be a potent inhibitor of the STAT1 signal, which could be a new molecular target for anti-inflammatory treatment, and may thus have therapeutic applications as an immune modulator in inflammatory diseases such as AD.

• Authors: G-J Kang, S-C Han, N-J Kang, D-H Koo, D-B Park, S-Y Eun, H-K Kang, E-S Yoo
• Journal: The British journal of dermatology (Br J Dermatol) Vol. 171 Issue 3 Pg. 512-23 (Sep 2014) ISSN: 1365-2133 [Electronic] England
• PMID: 24602010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 British Association of Dermatologists.

Chemical References

• CCL22 protein, human
• Chemokine CCL22
• Chromones
• Flavones
• Receptors, Interferon
• SOCS1 protein, human
• STAT1 Transcription Factor
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• interferon gamma receptor
• Interferon-gamma
• Janus Kinases
• quercetagetin

Topics

• Chemokine CCL22 (antagonists & inhibitors)
• Chromones (pharmacology)
• Flavones
• Humans
• Interferon-gamma (drug effects)
• Janus Kinases (drug effects)
• Keratinocytes (drug effects)
• Receptors, Interferon (drug effects)
• STAT1 Transcription Factor (drug effects)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins (drug effects)
• Transforming Growth Factor beta1 (drug effects)
• Tumor Necrosis Factor-alpha (drug effects)