JNK-1 deficiency limits macrophage-mediated antigen-induced arthritis.

Abstract

OBJECTIVE:

To elucidate the nonredundant roles of JNK-1 and JNK-2 in antigen-induced arthritis (AIA).

METHODS:

Mice that were genetically disrupted in Jnk1 or Jnk2 were primed by injection of methylated bovine serum albumin (mBSA) in Freund's complete adjuvant and then challenged on day 21 by intraarticular injection of mBSA into the right knee. Bone marrow chimeras were generated and similarly treated. Joints were harvested and prepared for histologic assessment. T cell responses were verified by cytokine and proliferation responses, and relative immunoglobulin responses were measured by enzyme-linked immunosorbent assay. Cytokine messenger RNA expression levels were measured by quantitative polymerase chain reaction analysis. Thioglycollate-elicited and zymosan A-elicited macrophage recruitment was tested in vivo, and cell migration was tested in vitro. The peptide inhibitor D-JNKi was injected daily starting 4 days after intraarticular injection of mBSA into wild-type (WT) mice, and inflammation was scored histologically.

RESULTS:

JNK-1-deficient, but not JNK-2-deficient, mice had a reduction in inflammatory cell infiltration and joint damage. This effect was primarily restricted to hematopoietic cells, but B and T cell responses were preserved in mBSA-injected mice. JNK-1-deficient macrophages produced cytokines and chemokines at a level comparable to that in their WT counterparts. However, macrophage migration was impaired in vivo and in vitro. Targeting JNK with the peptide inhibitor D-JNKi dramatically reduced inflammation and joint destruction in WT mice.

CONCLUSION:

AIA is dependent on JNK-1, but not JNK-2. JNK-1 is a promising molecular target for reducing autoimmune inflammation, since its inhibition impairs macrophage migration.

• Authors: Monica Guma, Lisa M Ronacher, Gary S Firestein, Michael Karin, Maripat Corr
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 63 Issue 6 Pg. 1603-12 (Jun 2011) ISSN: 1529-0131 [Electronic] United States
• PMID: 21305529 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 by the American College of Rheumatology.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Immunoglobulins
• Peptides
• Thioglycolates
• methylated bovine serum albumin
• Serum Albumin, Bovine
• Freund's Adjuvant
• Zymosan
• Mitogen-Activated Protein Kinase 9
• Mitogen-Activated Protein Kinase 8
• D-JNKI-1

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Arthritis, Experimental (genetics, pathology)
• Bone Marrow (drug effects, immunology, pathology)
• Cell Movement (drug effects, immunology)
• Chimera (immunology)
• Cytokines (immunology)
• Female
• Freund's Adjuvant (immunology)
• Immunoglobulins (immunology)
• Knee Joint (drug effects, immunology, pathology)
• Macrophages (enzymology, immunology)
• Mice
• Mice, Congenic
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 8 (genetics)
• Mitogen-Activated Protein Kinase 9 (genetics)
• Peptides (immunology, pharmacology)
• Serum Albumin, Bovine (immunology)
• T-Lymphocytes (immunology)
• Thioglycolates (immunology)
• Zymosan (immunology)