Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The production of inflammatory cytokines is a highly regulated process involving transcriptional and posttranscriptional mechanisms. One of the major signaling pathways activated by periopathogenic LPS in p38 MARK. Following p38 phosphorylation, inactivation of p38 MAP kinases is achieved mainly by a family of dual-specific MAP kinase phosphatases (MKP). MKP-1 is capable of negatively regulating both transcriptional and post transcriptional p38 MAP kinase activity. MKP-1 contributes towards LPS tolerance and over-expression of MKP-1 has shown to accelerate p38 inactivation resulting in diminished proinflammatory cytokine production. We have recently shown that LPS-induced IL-6 mRNA stability expression requires p38 signaling. Preliminary data for this proposal indicates that in MKP- 1 transfected cells, LPS-induced IL-6 expression is significantly attenuated. In addition, we have provided significant data showing the p38 is a major signaling pathway contributing to LPS-induced periodontal bone destruction. Based upon these data, we hypothesize that the endogenous negative regulator mechanism of p38 signaling, MKP-1, is a key component of responsible for attenuation of LPS-induced inflammatory cytokine expression in macrophages. In this proposal, the ability of TIP over-expression to decrease inflammation will be determined in vitro using gene targeted strategies in macrophages, and in vivo using experimental periodontitis models.
The specific aims are 1) To determine the role of over-expressed MKP-1 on IL-6 and TNFa mRNA expression in vitro. 2) To determine the contribution of MKP-1 in ontogeny of inflammatory cytokine production and LPS-induced osteoclastogenesis in primary bone marrow macrophages and 3) To determine the impact of MKP-1 in inflammatory bone destruction in vivo using MKP mice. These studies will establish the role of LPS-induced cytokine expression and negative regulation in inflammatory bone loss through selective attenuation of p38 MAPK-induced signaling in periodontal bone destruction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018290-05
Application #
7760622
Study Section
Special Emphasis Panel (ZDE1-YL (20))
Program Officer
Lumelsky, Nadya L
Project Start
2007-02-07
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$332,163
Indirect Cost
Name
Medical University of South Carolina
Department
Type
Schools of Dentistry
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Valerio, Michael S; Herbert, Bethany A; Basilakos, Dimitrios S et al. (2015) Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2. Cytokine 71:71-80
Valerio, Michael S; Herbert, Bethany A; Griffin 3rd, Alfred C et al. (2014) MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation. Bone 60:16-25
Zhang, Xiaoyi; Hyer, J Madison; Yu, Hong et al. (2014) DUSP1 phosphatase regulates the proinflammatory milieu in head and neck squamous cell carcinoma. Cancer Res 74:7191-7
Intini, G; Katsuragi, Y; Kirkwood, K L et al. (2014) Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions. Adv Dent Res 26:38-46
Qin, Zhiqiang; Dai, Lu; Defee, Michael et al. (2013) Kaposi's sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection. J Virol 87:621-35
Travan, Suncica; Li, Fei; D'Silva, Nisha J et al. (2013) Differential expression of mitogen activating protein kinases in periodontitis. J Clin Periodontol 40:757-64
Zhang, Xiaoyi; Junior, Carlos Rossa; Liu, Min et al. (2013) Oral squamous carcinoma cells secrete RANKL directly supporting osteolytic bone loss. Oral Oncol 49:119-28
Guimaraes, Morgana Rodrigues; Leite, Fabio Renato Manzoli; Spolidorio, Luis Carlos et al. (2013) Curcumin abrogates LPS-induced pro-inflammatory cytokines in RAW 264.7 macrophages. Evidence for novel mechanisms involving SOCS-1, -3 and p38 MAPK. Arch Oral Biol 58:1309-17
Griffin 3rd, Alfred C; Kern, Michael J; Kirkwood, Keith L (2012) MKP-1 is essential for canonical vitamin D-induced signaling through nuclear import and regulates RANKL expression and function. Mol Endocrinol 26:1682-93
Ge, Chunxi; Yang, Qian; Zhao, Guisheng et al. (2012) Interactions between extracellular signal-regulated kinase 1/2 and p38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J Bone Miner Res 27:538-51

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