Thalidomide ameliorates rosacea-like skin inflammation and suppresses NF-κB activation in keratinocytes

Mengting Chen; Hongfu Xie; Zhaohui Chen; San Xu; Ben Wang; Qinqin Peng; Ke Sha; Wenqin Xiao; Tangxiele Liu; Yiya Zhang; Ji Li; Zhili Deng

doi:10.1016/j.biopha.2019.109011

Thalidomide ameliorates rosacea-like skin inflammation and suppresses NF-κB activation in keratinocytes

Biomed Pharmacother. 2019 Aug:116:109011. doi: 10.1016/j.biopha.2019.109011. Epub 2019 May 25.

Authors

Mengting Chen¹, Hongfu Xie², Zhaohui Chen³, San Xu⁴, Ben Wang⁵, Qinqin Peng⁴, Ke Sha⁴, Wenqin Xiao⁴, Tangxiele Liu⁴, Yiya Zhang⁶, Ji Li⁷, Zhili Deng⁸

Affiliations

¹ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
³ Department of Dermatology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
⁴ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁵ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁶ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, Hunan, China.
⁷ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, Hunan, China; Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁸ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, Hunan, China; Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: dengzhili@csu.edu.cn.

PMID: 31132668
DOI: 10.1016/j.biopha.2019.109011

Abstract

Background: Rosacea is a chronic inflammatory skin disorder of uncertain etiology. Evidence suggests the underlying pathogenesis is modulated by abnormal inflammatory and vascular responses. Thalidomide is a synthetic derivative acid with anti-inflammatory and anti-angiogenic properties. However, its effects on rosacea remain unknown.

Objectives: To investigate the effects of thalidomide on the lesional alterations and molecular mechanisms in rosacea.

Methods: Mice were intradermally injected with LL37 to induce rosacea-like features and intraperitoneally administered with thalidomide. The severity of skin inflammation was evaluated. The mRNA levels of cytokines and chemokines associated with rosacea were assessed by qPCR. The number of CD4 positive infiltrated T helper cells and CD31 positive microvessels, and related-genes were measured by immunoﬂuorescence, qPCR and ELISA. Moreover, the effect of thalidomide on inhibiting NF-κB activation was determined by immunoﬂuorescence and western blot.

Results: Our results showed that thalidomide significantly alleviated erythema and reduced inflammatory cell infiltration in dermis of LL37-induced rosacea-like mice. The production of cytokines and chemokines induced by LL37 was decreased by thalidomide in mice skin and HaCaT keratinocytes. Particularly, we showed thalidomide reduced CD4⁺ T helper cell infiltration and downregulated Th1- and Th17-polarizing genes. In addition, thalidomide treatment lowered the microvessel density and vascular endothelial growth factor (VEGF) expression. We further demonstrated that thalidomide suppressed NF-κB activation in LL37-treated skin and in TNF-α-stimulated HaCaT keratinocytes in vitro.

Conclusions: Our findings suggest thalidomide attenuates the inflammation and represses NF-κB activation in skin, which leads to assumptions that thalidomide may be a new therapeutic agent for rosacea.

Keywords: Angiogenesis; Inflammation; LL37; NF-κB; Rosacea; Thalidomide.

MeSH terms

Animals
Antimicrobial Cationic Peptides
Cathelicidins
Cell Line
Chemokines / biosynthesis
Humans
Inflammation / complications
Inflammation / drug therapy*
Inflammation / metabolism
Keratinocytes / drug effects
Keratinocytes / metabolism*
Keratinocytes / pathology*
Mice, Inbred BALB C
NF-kappa B / metabolism*
Neovascularization, Physiologic / drug effects
Rosacea / complications
Rosacea / drug therapy*
Rosacea / immunology
Rosacea / metabolism*
Skin / blood supply
Skin / drug effects
Skin / immunology
Skin / pathology*
Th1 Cells / drug effects
Th1 Cells / immunology
Th17 Cells / drug effects
Th17 Cells / immunology
Thalidomide / pharmacology
Thalidomide / therapeutic use*

Substances

Antimicrobial Cationic Peptides
Chemokines
NF-kappa B
Thalidomide
Cathelicidins