Mucosal IL-10 and TGF-β play crucial roles in preventing LPS-driven, IFN-γ-mediated epithelial damage in human colon explants

被引:126
作者
Jarry, Anne [1 ,2 ]
Bossard, Celine [1 ,2 ,3 ]
Bou-Hanna, Chantal [1 ,2 ]
Masson, Damien [1 ,2 ,3 ]
Espaze, Eric [2 ,3 ]
Denis, Marc G. [1 ,2 ,3 ]
Laboisse, Christian L. [1 ,2 ,3 ]
机构
[1] INSERM, U539, Fac Med, F-44035 Nantes 1, France
[2] Univ Nantes, Fac Med, Nantes, France
[3] CHU Nantes, F-44035 Nantes 01, France
关键词
D O I
10.1172/JCI32140
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
IL-10 is an immunomodulatory cytokine that plays an obligate role in preventing spontaneous enterocolitis in mice. However, little is known about IL-10 function in the human intestinal mucosa. We showed here that IL-10 was constitutively expressed and secreted by the human normal colonic mucosa, including epithelial cells. Depletion of IL-10 in mucosal explants induced both downregulation of the IL-10-inducible, immunosuppressive gene BCL3 and upregulation of IFN-gamma, TNF-alpha, and IL-17. Interestingly, TGF-beta blockade also strongly induced IFN-gamma production. In addition, the high levels of IFN-gamma produced upon IL-10 depletion were responsible for surface epithelium damage and crypt loss, mainly by apoptosis. Polymyxin B, used as a scavenger of endogenous LPS, abolished both IFN-gamma production and epithelial barrier disruption. Finally, adding a commensal bacteria strain to mucosa explant cultures depleted of both IL-10 and LPS reproduced the ability of endogenous LPS to induce IFN-gamma secretion. These findings demonstrate that IL-10 ablation leads to an endogenous IFN-gamma-mediated inflammatory response via LPS from commensal bacteria in the human colonic mucosa. We also found that both IL-10 and TGF-beta play crucial roles in maintaining human colonic mucosa homeostasis.
引用
收藏
页码:1132 / 1142
页数:11
相关论文
共 64 条
[1]  
*AG NAT ACCR EV SA, 2001, ANNPATHOL, V21, P184
[2]   An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation [J].
Asseman, C ;
Mauze, S ;
Leach, MW ;
Coffman, RL ;
Powrie, F .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (07) :995-1003
[3]   In situ expression of interleukin-10 in noninflamed human gut and in inflammatory bowel disease [J].
Autschbach, F ;
Braunstein, J ;
Helmke, B ;
Zuna, I ;
Schürmann, G ;
Niemir, ZI ;
Wallich, R ;
Otto, HF ;
Meuer, SC .
AMERICAN JOURNAL OF PATHOLOGY, 1998, 153 (01) :121-130
[4]   Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses [J].
Berg, DJ ;
Davidson, N ;
Kuhn, R ;
Muller, W ;
Menon, S ;
Holland, G ;
ThompsonSnipes, L ;
Leach, MW ;
Rennick, D .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (04) :1010-1020
[5]   Polymyxin B: An ode to an old antidote for endotoxic shock [J].
Bhor, VM ;
Thomas, CJ ;
Surolia, N ;
Surolia, A .
MOLECULAR BIOSYSTEMS, 2005, 1 (03) :213-222
[6]   The complete genome sequence of Escherichia coli K-12 [J].
Blattner, FR ;
Plunkett, G ;
Bloch, CA ;
Perna, NT ;
Burland, V ;
Riley, M ;
ColladoVides, J ;
Glasner, JD ;
Rode, CK ;
Mayhew, GF ;
Gregor, J ;
Davis, NW ;
Kirkpatrick, HA ;
Goeden, MA ;
Rose, DJ ;
Mau, B ;
Shao, Y .
SCIENCE, 1997, 277 (5331) :1453-+
[7]   Early functional effects of Clostridium difficile toxin A on human colonocytes [J].
Branka, JE ;
Vallette, G ;
Jarry, A ;
BouHanna, C ;
Lemarre, P ;
Van, PN ;
Laboisse, CL .
GASTROENTEROLOGY, 1997, 112 (06) :1887-1894
[8]   T cells of the human intestinal lamina propria are high producers of interleukin-10 [J].
Braunstein, J ;
Qiao, L ;
Autschbach, F ;
Schurmann, G ;
Meuer, S .
GUT, 1997, 41 (02) :215-220
[9]   Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms [J].
Bruewer, M ;
Luegering, A ;
Kucharzik, T ;
Parkos, CA ;
Madara, JL ;
Hopkins, AM ;
Nusrat, A .
JOURNAL OF IMMUNOLOGY, 2003, 171 (11) :6164-6172
[10]   Caspase cleavage of keratin 18 and reorganization of intermediate filaments during epithelial cell apoptosis [J].
Caulin, C ;
Salvesen, GS ;
Oshima, RG .
JOURNAL OF CELL BIOLOGY, 1997, 138 (06) :1379-1394