Article

Decreased collagen-induced arthritis severity and adaptive immunity in MKK-6-deficient mice.

University of California San Diego at La Jolla, CA 92093, USA.
Arthritis & Rheumatology (Impact Factor: 7.48). 09/2011; 64(3):678-87. DOI: 10.1002/art.33359
Source: PubMed

ABSTRACT The MAPK kinases MKK-3 and MKK-6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK-3 or MKK-6 deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK-3 and MKK-6 deficiency in the collagen-induced arthritis (CIA) model.
Wild-type (WT), MKK-3(-/-) , and MKK-6(-/-) mice were immunized with bovine type II collagen. Disease activity was evaluated by semiquantitative scoring, histologic assessment, and micro-computed tomography. Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. In vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinases (MMPs) was determined by quantitative polymerase chain reaction.
MKK-6 deficiency markedly reduced arthritis severity compared with that in WT mice, while the absence of MKK-3 had an intermediate effect. Joint damage was minimal in arthritic MKK-6(-/-) mice and intermediate in MKK-3(-/-) mice compared with WT mice. MKK-6(-/-) mice had modestly lower levels of pathogenic anticollagen antibodies than did WT or MKK-3(-/-) mice. In vitro T cell assays showed reduced proliferation and interleukin-17 (IL-17) production by lymph node cells from MKK-6(-/-) mice in response to type II collagen. Gene expression of synovial IL-6, MMP-3, and MMP-13 was significantly inhibited in MKK-6-deficient mice.
Reduced disease severity in MKK-6(-/-) mice correlated with decreased anticollagen antibody responses, indicating that MKK-6 is a crucial regulator of inflammatory joint destruction in CIA. MKK-6 is a potential therapeutic target in complex diseases involving adaptive immune responses, such as RA.

0 Bookmarks
 · 
109 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Conventional p38α inhibitors have limited efficacy in rheumatoid arthritis, possibly because p38 blockade suppresses the counter-regulatory mechanisms that limit inflammation. In contrast, targeting the upstream MAP kinase kinases, MKK3 and MKK6, partially maintains p38-mediated anti-inflammatory responses in bone marrow-derived macrophages (BMDM). In this study, we explored the mechanisms that preserve anti-inflammatory gene expression by evaluating differential regulation of IL-10 and p38-dependent anti-inflammatory genes in MKK3-/-, MKK6-/-, and p38 inhibitor-treated wildtype cells.
    Journal of inflammation (London, England). 01/2014; 11:14.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective. The role of most p38MAPK isoforms in inflammatory arthritis is not known. Here we evaluated p38γ and p38δ deficiency in the collagen-induced arthritis (CIA) model. Methods. In wild-type, p38γ(-/-) , p38δ(-/-) and p38γ/δ(-/-) mice immunized with chicken type II collagen, we evaluated disease activity by semiquantitative scoring and histological assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anti-collagen antibody levels by enzyme-linked immunosorbent assay. Cytokine and p38MAPK isoform expression in joints were determined by quantitative polymerase chain reaction. Results. Compound p38γ and p38δ deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38γ or p38δ had an intermediate effect. Joint damage was minimal in arthritic p38γ/δ(-/-) compared with WT mice. p38γ/δ(-) (/-) mice had lower levels of pathogenic anti-collagen antibodies and of interleukin (IL)-1β and tumour necrosis factor-α than controls. In vitro T cell assays showed reduced proliferation, interferon (IFN)γ and IL-17 production by lymph node cells from p38γ/δ(-/-) mice. mRNA expression of IL-17 and IFNγ in joints was significantly inhibited in p38γ/δ(-/-) mice. WT chimeric mice with p38γ/δ(-/-) bone marrow did not show decreased CIA. Conclusion. Reduced disease severity in p38γ/δ(-/-) mice was associated with lower cytokine production and anti-collagen antibody responses than in controls, indicating that p38γ and p38δ are crucial regulators of inflammatory joint destruction in CIA. p38γ and p38δ are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 12/2013; · 7.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3-/- cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3-/- and MKK6-/- mice by micro-CT analysis. Bone loss was partially inhibited in MKK3-/- as well as MKK6-/- mice, despite normal osteoclastogenesis in MKK6-/- cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.
    PLoS ONE 01/2014; 9(1):e84818. · 3.73 Impact Factor

Full-text (2 Sources)

View
0 Downloads
Available from
Jul 11, 2014