Interleukin-10 Targets P38 MAPK to Modulate ARE-dependent TNF MRNA Translation and Limit Intestinal Pathology

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2001 Jul 12

PMID 11447117

Citations 82

Authors

D Kontoyiannis

A Kotlyarov

E Carballo

L Alexopoulou

P J Blackshear

M Gaestel

R Davis

R Flavell

G Kollias

Affiliations

Soon will be listed here.

Abstract

Interleukin-10 (IL-10) is a key inhibitory signal of inflammatory responses that regulates the production of potentially pathogenic cytokines like tumor necrosis factor (TNF). We show here that the development of chronic intestinal inflammation in IL-10-deficient mice requires the function of TNF, indicating that the IL-10/TNF axis regulates mucosal immunity. We further show that IL-10 targets the 3' AU-rich elements (ARE) of TNF mRNA to inhibit its translation. Moreover, IL-10 does not alter TNF mRNA stability, and its action does not require the presence of the stability-regulating ARE binding factor tristetraprolin, indicating a differential assembly of stability and translation determinants on the TNF ARE. Inhibition of TNF translation by IL-10 is exerted mainly by inhibition of the activating p38/MAPK-activated protein kinase-2 pathway. These results demonstrate a physiologically significant cross-talk between the IL-10 receptor and the stress-activated protein kinase modules targeting TNF mRNA translation. This cross-talk is necessary for optimal TNF production and for the maintenance of immune homeostasis in the gut.

Citing Articles

Mathematical model of the inflammatory response to acute and prolonged lipopolysaccharide exposure in humans.

Relouw F, Kox M, Taal H, Koch B, Prins M, Van Riel N NPJ Syst Biol Appl. 2024; 10(1):146.

PMID: 39638779 PMC: 11621538. DOI: 10.1038/s41540-024-00473-y.

IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history.

Bongartz H, Bradfield C, Gross J, Fraser I, Nita-Lazar A, Meier-Schellersheim M bioRxiv. 2024; .

PMID: 38654826 PMC: 11037870. DOI: 10.1101/2024.03.28.587272.

Mechanistic Study of Fruit Mixture Based on Network Pharmacology, Molecular Docking and Experimental Validation to Improve the Inflammatory Response of DKD Through AGEs/RAGE Signaling Pathway.

Li H, Dong A, Li N, Ma Y, Zhang S, Deng Y Drug Des Devel Ther. 2023; 17:613-632.

PMID: 36875720 PMC: 9983444. DOI: 10.2147/DDDT.S395512.

Molecular and cellular mechanisms underlying postoperative paralytic ileus by various immune cell types.

Sui C, Tao L, Bai C, Shao L, Miao J, Chen K Front Pharmacol. 2022; 13:929901.

PMID: 35991871 PMC: 9385171. DOI: 10.3389/fphar.2022.929901.

Effects of Seasonal Heat Stress during Late Gestation on Growth Performance, Metabolic and Immuno-Endocrine Parameters of Calves.

Tang C, Liang Y, Guo J, Wang M, Li M, Zhang H Animals (Basel). 2022; 12(6).

PMID: 35327113 PMC: 8944852. DOI: 10.3390/ani12060716.

References

Brown C, Lagnado C, Vadas M, Goodall G . Differential regulation of the stability of cytokine mRNAs in lipopolysaccharide-activated blood monocytes in response to interleukin-10. J Biol Chem. 1996; 271(33):20108-12. DOI: 10.1074/jbc.271.33.20108. View

Donnelly R, Dickensheets H, Finbloom D . The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res. 1999; 19(6):563-73. DOI: 10.1089/107999099313695. View

Rennick D, Fort M, Davidson N . Studies with IL-10-/- mice: an overview. J Leukoc Biol. 1997; 61(4):389-96. DOI: 10.1002/jlb.61.4.389. View

Swantek J, Cobb M, Geppert T . Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK. Mol Cell Biol. 1997; 17(11):6274-82. PMC: 232478. DOI: 10.1128/MCB.17.11.6274. View

Carballo E, Lai W, Blackshear P . Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science. 1998; 281(5379):1001-5. DOI: 10.1126/science.281.5379.1001. View

Erwig L, Kluth D, Walsh G, Rees A . Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines. J Immunol. 1998; 161(4):1983-8. View

Niiro H, Otsuka T, Ogami E, Yamaoka K, Nagano S, Akahoshi M . MAP kinase pathways as a route for regulatory mechanisms of IL-10 and IL-4 which inhibit COX-2 expression in human monocytes. Biochem Biophys Res Commun. 1998; 250(2):200-5. DOI: 10.1006/bbrc.1998.9287. View

Peschon J, Slack J, Reddy P, Stocking K, Sunnarborg S, Lee D . An essential role for ectodomain shedding in mammalian development. Science. 1998; 282(5392):1281-4. DOI: 10.1126/science.282.5392.1281. View

Gueydan C, Droogmans L, Chalon P, Huez G, Caput D, Kruys V . Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA. J Biol Chem. 1999; 274(4):2322-6. DOI: 10.1074/jbc.274.4.2322. View

10.

Takeda K, Clausen B, Kaisho T, Tsujimura T, Terada N, Forster I . Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity. 1999; 10(1):39-49. DOI: 10.1016/s1074-7613(00)80005-9. View

11.

Kishore R, Tebo J, Kolosov M, Hamilton T . Cutting edge: clustered AU-rich elements are the target of IL-10-mediated mRNA destabilization in mouse macrophages. J Immunol. 1999; 162(5):2457-61. View

12.

Kontoyiannis D, Pasparakis M, Pizarro T, Cominelli F, Kollias G . Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999; 10(3):387-98. DOI: 10.1016/s1074-7613(00)80038-2. View

13.

Lu H, Yang D, Wysk M, Gatti E, Mellman I, Davis R . Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 1999; 18(7):1845-57. PMC: 1171270. DOI: 10.1093/emboj/18.7.1845. View

14.

Levings M, Schrader J . IL-4 inhibits the production of TNF-alpha and IL-12 by STAT6-dependent and -independent mechanisms. J Immunol. 1999; 162(9):5224-9. View

15.

Wang S, Pawlowski J, Wathen S, Kinney S, Lichenstein H, Manthey C . Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase. Inflamm Res. 1999; 48(10):533-8. DOI: 10.1007/s000110050499. View

16.

Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk H . MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol. 1999; 1(2):94-7. DOI: 10.1038/10061. View

17.

Bode J, Nimmesgern A, Schmitz J, Schaper F, Schmitt M, Frisch W . LPS and TNFalpha induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages. FEBS Lett. 1999; 463(3):365-70. DOI: 10.1016/s0014-5793(99)01662-2. View

18.

Osman F, Jarrous N, KAEMPFER R . A cis-acting element in the 3'-untranslated region of human TNF-alpha mRNA renders splicing dependent on the activation of protein kinase PKR. Genes Dev. 2000; 13(24):3280-93. PMC: 317206. DOI: 10.1101/gad.13.24.3280. View

19.

Ono K, Han J . The p38 signal transduction pathway: activation and function. Cell Signal. 2000; 12(1):1-13. DOI: 10.1016/s0898-6568(99)00071-6. View

20.

Beutler B . Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol. 2000; 12(1):20-6. DOI: 10.1016/s0952-7915(99)00046-1. View