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The dual specific phosphatase, MAP kinase phosphatase-2 (MKP-2) has recently been demonstrated to negatively regulate macrophage arginase-1 expression, while at the same time to positively regulate iNOS expression. Consequently, MKP-2 is likely to play a significant role in the host interplay with intracellular pathogens. Here we demonstrate that MKP-2 −/−  mice on the C57BL/6 background have enhanced susceptibility compared with wild-type counterparts following infection with type-2 strains of  Toxoplasma gondii  as measured by increased parasite multiplication during acute infection, increased mortality from day 12 post-infection onwards and increased parasite burdens in the brain, day 30 post-infection. MKP-2 −/−  mice did not, however, demonstrate defective type-1 responses compared with MKP-2 +/+  mice following infection although they did display significantly reduced serum nitrite levels and enhanced tissue arginase-1 expression. Early resistance to  T. gondii  in MKP-2 +/+ , but not MKP-2 −/− , mice was nitric oxide (NO) dependent as infected MKP-2 +/+ , but not MKP-2 −/−  mice succumbed within 10 days post-infection with increased parasite burdens following treatment with the iNOS inhibitor L-NAME. Conversely, treatment of infected MKP-2 −/−  but not MKP-2 +/+  mice with nor-NOHA increased parasite burdens indicating a protective role for arginase-1 in MKP-2 −/−  mice. In vitro studies using tachyzoite-infected bone marrow derived macrophages and selective inhibition of arginase-1 and iNOS activities confirmed that both iNOS and arginase-1 contributed to inhibiting parasite replication. However, the effects of arginase-1 were transient and ultimately the role of iNOS was paramount in facilitating long-term inhibition of parasite multiplication within macrophages.

MAP Kinase Phosphatase-2 Plays a Key Role in the Control of Infection with Toxoplasma gondii by Modulating iNOS and Arginase-1 Activities in Mice