Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis.

Abstract

p38 mitogen-activated protein kinase (MAPK) regulates cytokines in arthritis and is, in turn, regulated by MAPK kinase (MKK) 3 and MKK6. To modulate p38 function but potentially minimize toxicity, we evaluated the utility of targeting MKK3 by using MKK3(-/-) mice. These studies showed that TNF-alpha increased phosphorylation of p38 in WT cultured synoviocytes but that p38 activation, IL-1beta, and IL-6 expression were markedly lower in MKK3(-/-) synoviocytes. In contrast, IL-1beta or LPS-stimulated p38 phosphorylation and IL-6 production by MKK3(-/-) synoviocytes were normal. Detailed signaling studies showed that NF-kappaB also contributes to IL-6 production and that TNF-alpha-induced NF-kappaB activation is MKK3-dependent. In contrast, LPS-mediated activation of NF-kappaB does not require MKK3. To determine whether this dichotomy occurs in vivo, two inflammation models were studied. In K/BxN passive arthritis, the severity of arthritis was dramatically lower in MKK3(-/-) mice. Phospho-p38, phospho-MAPK activator protein kinase 2, IL-1beta, CXC ligand 1, IL-6, and matrix metalloproteinase (MMP) 3 levels in the joints of MKK3(-/-) mice were significantly lower than in controls. Exogenous IL-1beta administered during the first 4 days of the passive model restored arthritis to the same severity as in WT mice. In the second model, IL-6 production after systemic LPS administration was similar in WT and MKK3(-/-) mice. Therefore, selective MKK3 deficiency can suppress inflammatory arthritis and cytokine production while Toll-like receptor 4-mediated host defense remains intact.

• Authors: Tomoyuki Inoue, David L Boyle, Maripat Corr, Deepa Hammaker, Roger J Davis, Richard A Flavell, Gary S Firestein
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 14 Pg. 5484-9 (Apr 04 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16567640 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-1
• Interleukin-6
• NF-kappa B
• Tumor Necrosis Factor-alpha
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 3
• Map2k3 protein, mouse

Topics

• Animals
• Arthritis, Experimental (enzymology)
• Blotting, Western
• Electrophoretic Mobility Shift Assay
• Enzyme Activation
• Enzyme-Linked Immunosorbent Assay
• Immunoprecipitation
• Interleukin-1 (biosynthesis)
• Interleukin-6 (biosynthesis)
• MAP Kinase Kinase 3 (metabolism)
• Mice
• NF-kappa B (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)