Tài liệu Báo cáo khoa học: Expression and secretion of interleukin-1b, tumour necrosis factor-a and

Expression and secretion of interleukin-1b, tumour

necrosis factor-a and interleukin-10 by hypoxia- and

serum-deprivation-stimulated mesenchymal stem cells

Implications for their paracrine roles

Zongwei Li, Hua Wei, Linzi Deng, Xiangfeng Cong and Xi Chen

Research Center for Cardiac Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

Introduction

Ischaemic heart disease is a life-threatening condition

that may cause sudden cardiac failure and death.

Many researchers have investigated cell transplantation

as an alternative treatment for heart disease. Bone

marrow-derived mesenchymal stem cells (MSCs) are

easily obtainable and expandable, multipotent progeni￾tor cells [1] that have emerged as attractive candidates

for cellular therapies for heart and other organ-system

disorders [2]. Although several mechanisms have been

proposed for the cardioprotective effects of MSCs,

including cardiomyocyte regeneration, spontaneous cell

fusion and paracrine action [3], there is a growing

Keywords

IL-10; IL-1b; mesenchymal stem cell;

paracrine; TNF-a

Correspondence

X. Chen; X. Cong, Research Center for

Cardiac Regenerative Medicine, The

Ministry of Health, Cardiovascular Institute

& Fu Wai Hospital, Chinese Academy of

Medical Sciences & Peking Union Medical

College, 167 Beilishilu, Beijing 100037,

China

Fax ⁄ Tel: +86 10 88398584

E-mail: [email protected];

[email protected]

(Received 26 April 2010, revised 27 June

2010, accepted 10 July 2010)

doi:10.1111/j.1742-4658.2010.07770.x

To understand the potential paracrine roles of interleukin-1b (IL-1b),

tumour necrosis factor-a (TNF-a) and interleukin-10 (IL-10), the expres￾sion and secretion of these factors by rat bone marrow-derived mesenchy￾mal cells stimulated by hypoxia (4% oxygen) and serum deprivation

(hypoxia ⁄ SD) were investigated. We found that hypoxia ⁄ SD induced

nuclear factor kappa Bp65-dependent IL-1b and TNF-a transcription. Fur￾thermore, hypoxia ⁄ SD stimulated the translation of pro-IL-1b and its

processing to mature IL-1b, although the translation of TNF-a was

unchanged. Unexpectedly, the release of IL-1b and TNF-a from hypox￾ia ⁄ SD-stimulated mesenchymal cells was undetectable unless ATP or lipo￾polysaccharide was present. This result suggests that IL-1b and TNF-a are

not responsible for the paracrine effects of mesenchymal cells under ischae￾mic conditions. We also found that hypoxia ⁄ SD induced the transcription

and secretion of IL-10, which were significantly enhanced by lipopolysac￾charide and the proteasomal inhibitor MG132. Moreover, both the condi￾tioned medium from hypoxia ⁄ SD-stimulated mesenchymal cells (MSC-CM)

and IL-10 efficiently inhibited cardiac fibroblast proliferation and collagen

expression in vitro, suggesting that mesenchymal cell-secreted IL-10 pre￾vents cardiac fibrosis in a paracrine manner under ischaemic conditions.

Taken together, these findings may improve understanding of the cellu￾lar and molecular basis of the anti-inflammatory and paracrine effects of

mesenchymal cells.

Abbreviations

BrdU, 5-bromodeoxyuridine; DMEM, Dulbecco’s modified Eagle’s medium; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular

signal-regulated kinase; hypoxia ⁄ SD, hypoxia and serum deprivation; IL, interleukin; IMDM, Iscove’s modified Dulbecco’s medium;

LPS, lipopolysaccharide; MSCs, mesenchymal stem cells; NF-jBp65, nuclear factor kappa Bp65; p38, p38 mitogen-activated protein kinase;

TNF-a, tumour necrosis factor-a.

3688 FEBS Journal 277 (2010) 3688–3698 ª 2010 The Authors Journal compilation ª 2010 FEBS