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

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. © 2013 woods et al.