Sexual Dimorphism in Periapical Inflammation and Bone Loss from Mitogen-activated Protein Kinase Phosphatase-1 Deficient Mice

The neurite outgrowth inhibitor protein Nogo is one of 300 proteins that contain a reticulon homology domain, which is responsible for their association with the endoplasmic reticulum. Here we have found that the Nogo-B spliceform becomes phosphorylated at Ser107 in response to lipopolysaccharide in RAW264 macrophages or anisomycin in HeLa cells. The phosphorylation is prevented by SB 203580, an inhibitor of SAPK2a (stress-activated protein kinase 2a)/p38α and SAPK2b/p38β, and does not occur in embryonic fibroblasts generated from SAPK2a/p38α-deficient mice. Nogo-B is phosphorylated at Ser107in vitro by MAPKAP-K2 [MAPK (mitogen-activated protein kinase)-activated protein kinase-2] or MAPKAP-K3, but not by other protein kinases that are known to be activated by SAPK2a/p38α. The anisomycin-induced phosphorylation of Ser107 in HeLa cells can be prevented by ‘knockdown’ of MAPKAP-K2 using siRNA (small interfering RNA). Taken together, our results identify Nogo-B as a new physiological substrate of MAPKAP-K2.

Download Full-text

The Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinases MK2 and MK3 Cooperate in Stimulation of Tumor Necrosis Factor Biosynthesis and Stabilization of p38 MAPK

Molecular and Cellular Biology ◽

10.1128/mcb.01456-06 ◽

2006 ◽

Vol 27 (1) ◽

pp. 170-181 ◽

Cited By ~ 159

Author(s):

N. Ronkina ◽

A. Kotlyarov ◽

O. Dittrich-Breiholz ◽

M. Kracht ◽

E. Hitti ◽

...

Keyword(s):

Protein Kinase ◽

Tumor Necrosis Factor ◽

Protein Kinases ◽

Tumor Necrosis ◽

Mitogen Activated Protein Kinase ◽

Double Knockout ◽

Mitogen Activated Protein ◽

Deficient Mice ◽

Necrosis Factor

ABSTRACT MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

Download Full-text

Mitogen-Activated Protein Kinase 2 Signaling Shapes Macrophage Plasticity in Aggregatibacter actinomycetemcomitans-Induced Bone Loss

Infection and Immunity ◽

10.1128/iai.00552-16 ◽

2016 ◽

Vol 85 (1) ◽

Cited By ~ 5

Author(s):

Bethany A. Herbert ◽

Heidi M. Steinkamp ◽

Matthias Gaestel ◽

Keith L. Kirkwood

Keyword(s):

Protein Kinase ◽

Bone Loss ◽

Periodontal Disease ◽

Alveolar Bone ◽

Aggregatibacter Actinomycetemcomitans ◽

Osteoclast Formation ◽

Mitogen Activated Protein Kinase ◽

Micro Computed Tomography ◽

Content Type ◽

Mitogen Activated Protein

ABSTRACT Aggregatibacter actinomycetemcomitans is associated with aggressive periodontal disease, which is characterized by inflammation-driven alveolar bone loss. A. actinomycetemcomitans activates the p38 mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase 2 (MK2) stress pathways in macrophages that are involved in host responses. During the inflammatory process in periodontal disease, chemokines are upregulated to promote recruitment of inflammatory cells. The objective of this study was to determine the role of MK2 signaling in chemokine regulation during A. actinomycetemcomitans pathogenesis. Utilizing a murine calvarial model, Mk2 +/+ and Mk2 −/− mice were treated with live A. actinomycetemcomitans bacteria at the midsagittal suture. MK2 positively regulated the following macrophage RNA: Emr1 (F4/80), Itgam (CD11b), Csf1r (M-CSF Receptor), Itgal (CD11a), Tnf, and Nos2. Additionally, RNA analysis revealed that MK2 signaling regulated chemokines CCL3 and CCL4 in murine calvarial tissue. Utilizing the chimeric murine air pouch model, MK2 signaling differentially regulated CCL3 and CCL4 in the hematopoietic and nonhematopoietic compartments. Bone resorption pits in calvaria, observed by micro-computed tomography, and osteoclast formation were decreased in Mk2 −/− mice compared to Mk2 +/+ mice after A. actinomycetemcomitans treatment. In conclusion, these data suggest that MK2 in macrophages contributes to regulation of chemokine signaling during A. actinomycetemcomitans-induced inflammation and bone loss.

Download Full-text