MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis.
TNF-alpha is a pleiotropic cytokine considered a primary mediator of immune regulation and inflammatory response and has been shown to play a central role in rheumatoid arthritis (RA). MAPKAP kinase 2 (MK2) is a serine/threonine kinase that is regulated through direct phosphorylation by p38 MAPK, and has been shown to be an essential component in the inflammatory response that regulates the biosynthesis of TNF-alpha at a posttranscriptional level. The murine model of collagen-induced arthritis (CIA) is an established disease model to study pathogenic mechanisms relevant to RA. In this study, we report that deletion of the MK2 gene in DBA/1LacJ mice confers protection against CIA. Interestingly, the MK2 heterozygous mutants display an intermediate level of protection when compared with homozygous mutant and wild-type littermates. We show that MK2(-/-) and MK2(+/-) mice exhibit decreased disease incidence and severity in the CIA disease model and reduced TNF-alpha and IL-6 serum levels following LPS/d-Gal treatment compared with wild-type mice. Additionally, we show that levels of IL-6 mRNA in paws of mice with CIA correlate with the disease status. These findings suggest that an MK2 inhibitor could be of great therapeutic value to treat inflammatory diseases like RA.
Hegen
Martin
M
Inflammation Department, Wyeth Research, Cambridge, MA 02140, USA. Mhegen@wyeth.com
Gaestel
Matthias
M
Nickerson-Nutter
Cheryl L
CL
Lin
Lih-Ling
LL
Telliez
Jean-Baptiste
JB
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D001323:Autoantibodies / Q000096:biosynthesis; D002417:Cattle; D024043:Collagen Type II / Q000276:immunology*; D005552:Forelimb; D006580:Genetic Carrier Screening; D006614:Hindlimb; D007113:Immunity, Innate / Q000235:genetics; D015994:Incidence; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012720:Severity of Illness Index; D019914:Taq Polymerase / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D000099190:MAP-Kinase-Activated Kinase 2
D001323:Autoantibodies; D024043:Collagen Type II; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D019914:Taq Polymerase; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2