The role of MAP kinase phosphatase-1 in the protective mechanism of dexamethasone against endotoxemia.

AIMS: We have previously shown that glucocorticoids induce the expression of MAP kinase phosphatase (Mkp)(a)-1 in innate immune cells. Since Mkp-1 is a critical negative regulator of the innate immune response, we hypothesize that Mkp-1 plays a significant role in the anti-inflammatory action of glucocorticoids. The specific aim of the present study is to understand the role of Mkp-1 in the anti-inflammatory function of glucocorticoids. MAIN METHODS: Wild-type and Mkp-1(-/-) mice were treated with different doses of dexamethasone and then challenged with different doses of lipopolysaccharide (LPS). The survival and blood cytokines were assessed. The effects of dexamethasone on cytokine production in wild-type and Mkp-1(-/-) primary macrophages ex vivo were also examined. KEY FINDINGS: We found that dexamethasone induced the expression of Mkp-1 in vivo. Dexamethasone treatment completely protected wild-type mice from the mortality caused by a relatively high dose of LPS. However, dexamethasone treatment offered only a partial protection to Mkp-1(-/-) mice. Dexamethasone attenuated TNF-alpha production in both wild-type and Mkp-1(-/-) mice challenged with LPS, although TNF-alpha production in Mkp-1(-/-) mice was significantly more robust than that in wild-type mice. Dexamethasone pretreatment shortened the duration of p38 and JNK activation in LPS-stimulated wild-type macrophages, but had little effect on p38 or JNK activation in similarly treated Mkp-1(-/-) macrophages. SIGNIFICANCE: Our results indicate that the inhibition of p38 and JNK activities by glucocorticoids is mediated by enhanced Mkp-1 expression. These results demonstrate that dexamethasone exerts its anti-inflammatory effects through both Mkp-1-dependent and Mkp-1-indepent mechanisms.

Knockout of Mkp-1 enhances the host inflammatory responses to gram-positive bacteria.

MAPK phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAPK. We have previously demonstrated that MKP-1 acts as a negative regulator of p38 and JNK in immortalized macrophages after stimulation with peptidoglycan isolated from Gram-positive bacteria. To define the physiological function of MKP-1 during Gram-positive bacterial infection, we studied the innate immune responses to Gram-positive bacteria using Mkp-1 knockout (KO) mice. We found that Mkp-1(-/-) macrophages exhibited prolonged activation of p38 and JNK, but not of ERK, following exposure to either peptidoglycan or lipoteichoic acid. Compared with wild-type (WT) macrophages, Mkp-1(-/-) macrophages produced more proinflammatory cytokines such as TNF-alpha and IL-6. Moreover, after challenge with peptidoglycan, lipoteichoic acid, live or heat-killed Staphylococcus aureus bacteria, Mkp-1 KO mice also mounted a more robust production of cytokines and chemokines, including TNF-alpha, IL-6, IL-10, and MIP-1alpha, than did WT mice. Accordingly, Mkp-1 KO mice also exhibited greater NO production, more robust neutrophil infiltration, and more severe organ damage than did WT mice. Surprisingly, WT and Mkp-1 KO mice exhibited no significant difference in either bacterial load or survival rates when infected with live S. aureus. However, in response to challenge with heat-killed S. aureus, Mkp-1 KO mice exhibited a substantially higher mortality rate compared with WT mice. Our studies indicate that MKP-1 plays a critical role in the inflammatory response to Gram-positive bacterial infection. MKP-1 serves to limit the inflammatory reaction by inactivating JNK and p38, thus preventing multiorgan failure caused by exaggerated inflammatory responses.

Social and photoperiod effects on reproduction in five species of Peromyscus.

At temperate latitudes, mammals and birds use changes in day length to time their reproductive activities to coincide with seasonal fluctuations in the environment. Close to the equator, however, conditions permissive of breeding do not track changes in day length as well, so other cues may be more important than photoperiod. In a variety of vertebrates, social interactions regulate breeding condition. We hypothesized that individuals of different species of Peromyscus mice found closer to the equator would respond more strongly to housing with an opposite sex conspecific than they would to photoperiod. To test this hypothesis, we compared the effects of long and short day lengths versus 8 days of pair housing with a female on reproductive tissue weights and testosterone (T) concentrations in five species of Peromyscus (P. aztecus, P. eremicus, P. maniculatus, P. melanophrys, and P. polionotus). After 13 weeks of short days (8L:16D), P. maniculatus, P. melanophrys, and P. polionotus significantly reduced relative testes mass compared to long day (16L:8D) housed animals. Social housing, however, had no effect on tissue weights in any species. However, male P. polionotus paired with females for 8 days increased T concentrations compared to single-housed males, whereas paired P. maniculatus reduced T. These data suggest that mechanisms of photoperiodic and social regulation of reproductive function are mediated by different physiological mechanisms among closely-related species and that both phylogeny and environmental factors contribute to patterns of reproductive plasticity.