Meprin Metalloproteases Inactivate Interleukin 6
Meprins have been implicated in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, in which the cytokine IL-6 is a prominent effector molecule. Because IL-6 levels are elevated markedly in meprin α and α/β knockout mice in an experimental model of inflammatory b...
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Published in | The Journal of biological chemistry Vol. 289; no. 11; pp. 7580 - 7588 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
14.03.2014
American Society for Biochemistry and Molecular Biology |
Subjects | |
Online Access | Get full text |
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Summary: | Meprins have been implicated in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, in which the cytokine IL-6 is a prominent effector molecule. Because IL-6 levels are elevated markedly in meprin α and α/β knockout mice in an experimental model of inflammatory bowel disease, the interaction between meprins and IL-6 was studied. The results demonstrate that rodent and human meprin A and B cleave IL-6 to a smaller product and, subsequently, are capable of extensive degradation of the cytokine. Analysis of the limited degradation product formed by meprin A indicated that three to five amino acids are removed from the C terminus of the cytokine. Meprin A and meprin B cleaved IL-6 with micromolar affinities (Km of 4.7 and 12.0 μm, respectively) and with high efficiencies (kcat/Km of 0.2 and 2.5 (m−1/s−1) × 106, respectively). These efficiency constants are among the highest for known meprin substrates. Madin-Darby canine kidney cells transiently transfected with meprin α or meprin β constructs also cleave exogenous IL-6. Both human and murine IL-6 cleaved by meprin A or B are inactivated, as demonstrated by their decreased capability to stimulate proliferation of B9 cells. These results are consistent with the proposition that one function of meprin metalloproteases is to modulate inflammation by inactivating IL-6.
Background: Meprin metalloproteinases are implicated in the pathogenesis of inflammatory diseases where the cytokine IL-6 plays a role.
Results: Meprins cleave and decrease the biological activity of IL-6.
Conclusion: IL-6 activity at inflammatory sites is regulated in part by meprins.
Significance: Decreasing IL-6 bioactivity is an underlying mechanism for meprin regulation of inflammation. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Dept. of Microbiology and Immunology, Louisiana State University, Health Sciences Center, 1501 Kings Hwy., Shreveport, LA 71130. |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M113.546309 |