Essential Role for Mnk Kinases in Type II Interferon (IFNγ) Signaling and Its Suppressive Effects on Normal Hematopoiesis

IFNγ exhibits potent antitumor effects and plays important roles in the innate immunity against cancer. However, the mechanisms accounting for the antiproliferative effects of IFNγ still remain to be elucidated. We examined the role of Mnk1 (MAPK-interacting protein kinase 1) in IFNγ signaling. Our data demonstrate that IFNγ treatment of sensitive cells results in engagement of Mnk1, activation of its kinase domain, and downstream phosphorylation of the cap-binding protein eIF4E on Ser-209. Such engagement of Mnk1 plays an important role in IFNγ-induced IRF-1 (IFN regulatory factor 1) gene mRNA translation/protein expression and is essential for generation of antiproliferative responses. In studies aimed to determine the role of Mnk1 in the induction of the suppressive effects of IFNs on primitive hematopoietic progenitors, we found that siRNA-mediated Mnk1/2 knockdown results in partial reversal of the suppressive effects of IFNγ on human CD34+-derived myeloid (CFU-GM) and erythroid (BFU-E) progenitors. These findings establish a key role for the Mnk/eIF4E pathway in the regulatory effects of IFNγ on normal hematopoiesis and identify Mnk kinases as important elements in the control of IFNγ-inducible ISG mRNA translation. IFNγ exhibits potent antitumor effects and plays important roles in the innate immunity against cancer. However, the mechanisms accounting for the antiproliferative effects of IFNγ still remain to be elucidated. We examined the role of Mnk1 (MAPK-interacting protein kinase 1) in IFNγ signaling. Our data demonstrate that IFNγ treatment of sensitive cells results in engagement of Mnk1, activation of its kinase domain, and downstream phosphorylation of the cap-binding protein eIF4E on Ser-209. Such engagement of Mnk1 plays an important role in IFNγ-induced IRF-1 (IFN regulatory factor 1) gene mRNA translation/protein expression and is essential for generation of antiproliferative responses. In studies aimed to determine the role of Mnk1 in the induction of the suppressive effects of IFNs on primitive hematopoietic progenitors, we found that siRNA-mediated Mnk1/2 knockdown results in partial reversal of the suppressive effects of IFNγ on human CD34+-derived myeloid (CFU-GM) and erythroid (BFU-E) progenitors. These findings establish a key role for the Mnk/eIF4E pathway in the regulatory effects of IFNγ on normal hematopoiesis and identify Mnk kinases as important elements in the control of IFNγ-inducible ISG mRNA translation. IntroductionThe only known member of the Type II IFN family, IFNγ, plays an important role in the innate and adaptive immunity against microbial and viral infections and exhibits potent antitumor effects (1Isaacs A. Lindenmann J. Proc. R. Soc. Lond. B Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar, 2Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2249) Google Scholar, 3Borden E.C. Sen G.C. Uze G. Silverman R.H. Ransohoff R.M. Foster G.R. Stark G.R. Nat. Rev. Drug. Discov. 2007; 6: 975-990Crossref PubMed Scopus (859) Google Scholar, 4Schoenborn J.R. Wilson C.B. Adv. Immunol. 2007; 96: 41-101Crossref PubMed Scopus (1165) Google Scholar). IFNγ is a cytokine mainly secreted by T lymphocytes, activated natural killer cells, and antigen-presenting cells such as macrophages and dendritic cells (5Schroder K. Hertzog P.J. Ravasi T. Hume D.A. J. Leukocyte Biol. 2004; 75: 163-189Crossref PubMed Scopus (2847) Google Scholar, 6Boehm U. Klamp T. Groot M. Howard J.C. Annu. Rev. Immunol. 1997; 15: 749-795Crossref PubMed Scopus (2462) Google Scholar) and is known to elicit pleiotropic biological effects on cells and tissues. This cytokine enhances the activity of natural killer cells, facilitates class switching, and regulates immunoglobulin production by B cells (5Schroder K. Hertzog P.J. Ravasi T. Hume D.A. J. Leukocyte Biol. 2004; 75: 163-189Crossref PubMed Scopus (2847) Google Scholar, 6Boehm U. Klamp T. Groot M. Howard J.C. Annu. Rev. Immunol. 1997; 15: 749-795Crossref PubMed Scopus (2462) Google Scholar, 7Saha B. Jyothi Prasanna S. Chandrasekar B. Nandi D. Cytokine. 2010; 50: 1-14Crossref PubMed Scopus (226) Google Scholar). In addition, it regulates survival and proliferation of T cells, modulates the activity of antigen presenting cells and, under certain circumstances, can promote differentiation of several distinct cell types (5Schroder K. Hertzog P.J. Ravasi T. Hume D.A. J. Leukocyte Biol. 2004; 75: 163-189Crossref PubMed Scopus (2847) Google Scholar, 6Boehm U. Klamp T. Groot M. Howard J.C. Annu. Rev. Immunol. 1997; 15: 749-795Crossref PubMed Scopus (2462) Google Scholar, 7Saha B. Jyothi Prasanna S. Chandrasekar B. Nandi D. Cytokine. 2010; 50: 1-14Crossref PubMed Scopus (226) Google Scholar). Importantly, IFNγ facilitates immune responses to tumor cells, although it also inhibits angiogenesis and exerts direct anti-proliferative effects on a number of tumor cells (8Ikeda H. Old L.J. Schreiber R.D. Cytokine Growth Factor Rev. 2002; 13: 95-109Crossref PubMed Scopus (668) Google Scholar). Thus, considering the broad effects of IFNγ, understanding the cellular mechanisms that regulate its biological effects is highly relevant in advancing our overall understanding of the mechanisms of innate immunity against cancer and viral infections.Previous studies have established that IFNγ transduces signals by binding to its cell surface receptor, which is composed of two distinct subunits; the IFNγ receptor 1 and 2 chains, which are constitutively associated with the JAK family members JAK1 and JAK2 (reviewed in Refs. 2Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2249) Google Scholar and 3Borden E.C. Sen G.C. Uze G. Silverman R.H. Ransohoff R.M. Foster G.R. Stark G.R. Nat. Rev. Drug. Discov. 2007; 6: 975-990Crossref PubMed Scopus (859) Google Scholar). Binding of IFNγ to its receptor results in interactions between the receptor chains leading to the phosphorylation of the STAT1 transcriptional activator, followed by its dimerization, translocation to the nucleus, and activation of gene transcription by IFNγ-activated sequences (GAS) 2The abbreviations used are: GAS, IFNγ-activated sequences; MEF, mouse embryonic fibroblast; CFU-GM, colony forming unit-granulocyte monocyte; BFU-E, burst forming unit-erythroid. (2Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2249) Google Scholar, 3Borden E.C. Sen G.C. Uze G. Silverman R.H. Ransohoff R.M. Foster G.R. Stark G.R. Nat. Rev. Drug. Discov. 2007; 6: 975-990Crossref PubMed Scopus (859) Google Scholar). Beyond the classic JAK-STAT pathway, the transcriptional response to IFNγ also involves IFNγ-activated transcription elements (9Weihua X. Kolla V. Kalvakolanu D.V. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 103-108Crossref PubMed Scopus (56) Google Scholar) that are controlled by the transcription factor CCAAT enhancer-binding protein-β. Notably, the activity of CCAAT enhancer-binding protein-β is positively regulated by the MAP kinases Erk1 and Erk2 (10Hu J. Roy S.K. Shapiro P.S. Rodig S.R. Reddy S.P. Platanias L.C. Schreiber R.D. Kalvakolanu D.V. J. Biol. Chem. 2001; 276: 287-297Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). There has also protein kinase in the generation of cellular responses to regulates transcriptional by IFNγ J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Stark G.R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google the pathway plays an important role downstream of mRNA of S. A. B. S. B. Platanias L.C. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, S. A. B. M. Platanias L.C. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). family members and have also to important roles in IFNγ J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. B. H. A. Platanias L.C. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, A. B. A. S. S. A. Platanias L.C. J. Immunol. PubMed Scopus Google Scholar). is for important roles for in the induction of IFNγ responses A. A. S. A. S. M. K. Platanias L.C. J. Immunol. 2002; PubMed Scopus Google Scholar, M. A. D. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S.K. J. Shapiro P.S. Reddy S.P. Platanias L.C. G. J. Kalvakolanu D.V. Proc. Natl. Acad. Sci. U.S.A. 2002; PubMed Scopus Google Scholar, S. M. J. PubMed Scopus Google (MAPK-interacting protein 1 and 2 are activated engagement of the Type II IFN receptor and in the generation of IFNγ responses. Mnk1 is a downstream for the and and with the regulates phosphorylation of eIF4E R. T. J. 1997; PubMed Scopus Google Scholar, A. J. 1997; PubMed Scopus Google Scholar). Our data that IFNγ treatment results in activation of Mnk1 and its downstream eIF4E in an In studies cells, we found that Mnk activity is essential for mRNA of IRF-1 regulatory factor 1) and plays a role in the generation of responses by the Type II IFN our findings identify Mnk1 as a for mRNA of and generation of IFNγ antiproliferative studies we examined IFNγ of sensitive cells with human IFNγ for and cell by and with an that the of IFNγ treatment in of Mnk1, which and still treatment the of kinase in IFNγ signaling. We also examined IFNγ treatment regulates phosphorylation of the downstream of Mnk1, which is the Mnk phosphorylation in X. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.C. B. M. S.R. Biol. PubMed Scopus Google Scholar, G.C. M. Biol. 2001; PubMed Scopus Google Scholar, T. R. H. S. R. Biol. 2004; PubMed Scopus Google Scholar). in IFNγ treatment of cells in phosphorylation of eIF4E determine Mnk activity is essential for Type II phosphorylation of we examined such induction is in with of the Mnk1 and T. R. H. S. R. Biol. 2004; PubMed Scopus Google Scholar). and and with mouse IFNγ for in IFNγ treatment in phosphorylation of eIF4E in phosphorylation in the with in in which the effects of of Mnk in cells, we found that the phosphorylation of eIF4E is is for engagement of and and with mouse IFNγ for the of by followed by with an against eIF4E and with an against cells with for and with human IFNγ for the of by and with an against eIF4E and with an against to for activation of Mnk1 and eIF4E engagement of the Type II IFN Mnk1 has to be by the Erk1 and Erk2 kinases in response to X. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.C. B. M. S.R. Biol. PubMed Scopus Google Scholar, G.C. M. Biol. 2001; PubMed Scopus Google Scholar). We examined the phosphorylation of Mnk1 and in cells in the of the cells with and with IFNγ for the IFNγ has to in the engagement of Erk1 and Erk2 in A. Roy S. J. Kalvakolanu D.V. J. Immunol. 2005; PubMed Scopus Google Scholar, J. A. J. Immunol. PubMed Scopus Google Scholar). of In cells, Mnk1 and eIF4E by IFNγ, in cells, the activation of Mnk1 and eIF4E that the pathway is for activation of engagement of Mnk1 and eIF4E is cells with for and with human IFNγ for the of protein by and with against and with an against cells with for and with human IFNγ for the of by and with against Mnk1 against eIF4E and with against Mnk1 examined the role of Mnk1 as a of IFNγ We Mnk1 plays a role in the of of STAT1 and gene STAT1 phosphorylation by IFNγ on and in the of Mnk1 and in the of Mnk1 and and with transcriptional activation elements in that Mnk kinases roles in the control of IFNγ-induced STAT1 activation gene in the IFNγ-induced phosphorylation of STAT1 a the and of to be in and are for engagement of STAT1 activation of transcription and with IFNγ for the of cell by and with against STAT1 and with against signals for and STAT1 the in by and the of to STAT1 expression data are as the of of to STAT1 for and with IFNγ for the of cell by and with against STAT1 and with against signals for and STAT1 the in by and the of to STAT1 expression data are as the of of to STAT1 for and with an the cells with IFNγ for cells and for data are as in activity in response to IFNγ treatment control cells and the of the expression of the which plays an important role in the biological effects of IFNγ B. Jyothi Prasanna S. Chandrasekar B. Nandi D. Cytokine. 2010; 50: 1-14Crossref PubMed Scopus (226) Google Scholar). the of the Mnk pathway in the induction of IFNγ we examined and the effects of IFNγ on IRF-1 gene transcription and protein expression in Mnk1 and and IRF-1 protein IFNγ-inducible in such induction in the and IFNγ-inducible IRF-1 protein expression in cells with the Mnk These results that Mnk1/2 plays an important role in protein expression of mRNA expression for IRF-1 in the Mnk we a in effects in Mnk1 the an in Thus, although IRF-1 protein expression in response to IFNγ is in are of IRF-1 transcriptional expression in the Mnk cells, that a of mRNA for protein determine the role of the Mnk pathway in IRF-1 mRNA and with IFNγ for cells to and on a followed by the and IRF-1 mRNA induction by in IRF-1 mRNA in the that Mnk1 and important roles in of IRF-1 IRF-1 mRNA expression in studies Mnk1 of kinases in of Mnk1 and for IFNγ-induced protein cells with for followed by treatment with human IFNγ for the of by and with an against and the also with an against and with mouse IFNγ for the of by and with an against and the also with an against and with mouse expression of IRF-1 mRNA by as a data are as the induction and the of kinases are for IFNγ-induced mRNA translation. and with mouse cells to followed by on a and the is as a of for IRF-1 mRNA expression in the by for data are as in the and the of and in IFNγ-induced mRNA translation. and with mouse cells to followed by on a and the is as a of for IRF-1 mRNA expression in the by for data are as in the and the of we examined the effects of Mnk1 and in the generation of responses. cells with IFNγ, in the of the Mnk and colony in treatment with the Mnk the antiproliferative effects of IFNγ, a role for Mnk kinases in the generation of antiproliferative responses. we also used Mnk1 and the effects of on of colony There partial reversal of the suppressive effects of IFNγ on colony a for Mnk1 in the kinases the antiproliferative effects of IFNγ on cells in in with human IFNγ, in the of as and the data are as of control and the of for the of and IFNγ the of and cells with the and in a in the of human data are as of control colony and the of for the of control and IFNγ the of and for the of control and IFNγ the of and and for the of control and IFNγ the of and and also studies aimed the roles of Mnk1 and as of the suppressive effects of IFNγ on normal human cells with IFNγ in the of and normal myeloid (CFU-GM) erythroid (BFU-E) colony suppressive effects of IFNγ on by the Importantly, such reversal of responses also cells with Mnk1, a role for the Mnk pathway as a of the suppressive effects of IFNγ on normal kinases are essential for the generation of the effects of cells normal in in with human IFNγ, in the of as and in data are as of control colony cells and the of for the of and IFNγ the of and IFNγ for for the of and IFNγ the of and IFNγ for cells normal with the and in a in the of human IFNγ, as and in data are as of control colony control cells and the of for the of control and IFNγ the of Mnk1 and IFNγ for and for the of control and IFNγ the of Mnk1 and IFNγ for for the of control and IFNγ the of and IFNγ for and for the of control and IFNγ the of and IFNγ for for the of control and IFNγ the of Mnk1 and and IFNγ for and for the of control and IFNγ the of Mnk1 and and IFNγ for the has established the of Mnk kinases in and as of factor and signals M. 13: PubMed Scopus Google Scholar). for Mnk kinases is the factor which phosphorylation on T. R. H. S. R. Biol. 2004; PubMed Scopus Google Scholar, M. 13: PubMed Scopus Google Scholar). of eIF4E has in studies to be of in the of mRNA for certain as as for and cell proliferation A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. 2001; 15: PubMed Scopus Google Scholar, M. T. H. K. K. T. M. M. PubMed Scopus Google Scholar, Biol. 2010; PubMed Scopus Google Scholar, A. M. R. R. PubMed Scopus Google Scholar). Mnk kinases have also in the production of and in response to K. R. Cytokine. PubMed Scopus Google Scholar, R.M. M. J. PubMed Scopus Google studies have under certain circumstances, Mnk1 is in S. 2007; PubMed Scopus Google Scholar, L.C. M. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). of the Mnk/eIF4E pathway in established in a of which phosphorylation on K. A. M. Proc. Natl. Acad. Sci. U.S.A. 2010; PubMed Scopus Google Scholar). These studies that phosphorylation on is for in a cancer mouse K. A. M. Proc. Natl. Acad. Sci. U.S.A. 2010; PubMed Scopus Google Scholar). eIF4E phosphorylation on also found to with a of and in cancer K. A. M. Proc. Natl. Acad. Sci. U.S.A. 2010; PubMed Scopus Google Scholar). studies that Mnk1/2 activity is for tumor in the mouse T. M. K. R. Proc. Natl. Acad. Sci. U.S.A. 2010; PubMed Scopus Google the of the Mnk/eIF4E pathway in tumor only Type II IFNγ, exhibits pleiotropic biological and Acad. Sci. PubMed Scopus Google Scholar). This cytokine plays key roles in the generation of and in the immune against Acad. Sci. PubMed Scopus Google Scholar). IFNγ has also in PubMed Scopus Google Scholar) to PubMed Scopus Google Scholar) Cytokine Growth Factor Rev. PubMed Scopus Google Scholar). Such a of responses the and of cellular activated by the Type II IFN be that the Type II IFN receptor is and distinct the Type IFN receptor, and IFNγ has only with the family of Type IFNs S. Immunol. Rev. 2004; PubMed Scopus Google the we examined Mnk kinases are in by the Type II receptor and in the induction of Type II mRNA of regulated and generation of IFNγ responses. Our data demonstrate that Mnk1 is in an IFNγ-inducible in sensitive cells and regulates downstream phosphorylation of eIF4E on In studies for Mnk1 and we a for in the of mRNA of the IRF-1 gene and expression of the IRF-1 protein in Mnk1 a for the Mnk pathway in IRF-1 protein Notably, IRF-1 has to promote induction of in a of A. A. R. 2005; PubMed Scopus Google Scholar, Adv. Biol. PubMed Scopus Google Scholar, A. A. S. H. PubMed Scopus Google Scholar) and to an important role in the antiproliferative effects of IFNγ in cell A. Google Scholar) and in cells D. S. R. R. 2010; PubMed Scopus Google findings establish that the of Mnk kinases is essential for generation of the suppressive effects of IFNγ in normal human CD34+-derived erythroid (BFU-E) and myeloid (CFU-GM) progenitors, a and essential role for the pathway in the of normal hematopoiesis by on our regulatory effects of the Mnk pathway the for in IRF-1 mRNA studies have also that IRF-1 plays an important role in IFNγ-induced responses in normal human hematopoietic cells T. PubMed Google Scholar). Thus, as in the of Type IFNs S. S. K. K. T. R. R. Platanias L.C. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Mnk kinases to key and essential roles in mRNA of certain and generation of signals for antiproliferative responses and the of of the Mnk/eIF4E pathway in the generation of antiproliferative responses and suppressive effects on normal and hematopoiesis is in is pathway in and cell proliferation A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. 2001; 15: PubMed Scopus Google Scholar, M. T. H. K. K. T. M. M. PubMed Scopus Google Scholar, Biol. 2010; PubMed Scopus Google Scholar, A. M. R. R. PubMed Scopus Google Scholar, K. A. M. Proc. Natl. Acad. Sci. U.S.A. 2010; PubMed Scopus Google Scholar, T. M. K. R. Proc. Natl. Acad. Sci. U.S.A. 2010; PubMed Scopus Google Scholar). is in to and pathway is used in a by the Type II IFN receptor for mRNA of such as that responses. of gene transcription by JAK-STAT and engagement of the Mnk/eIF4E pathway to expression of that Importantly, it is that the Type II IFN receptor with factor for of pathway, of a pathway essential for responses and to are known to regulate the of several and Mnk1 is in the phosphorylation of the protein M. S. R. J. 2005; Full Text Full Text PDF PubMed Scopus Google as as of which are that with the mRNA M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, Mnk1 a of J. D. Biol. PubMed Scopus Google Scholar). phosphorylation of 2 by Mnk1 regulates its and its an important control for activation of the pathway by J. D. Biol. PubMed Scopus Google Scholar). Mnk1 has to on in its activation and M. S. D. J.R. A. R. T. S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of such by the IFNγ receptor and that such have in hematopoietic to be examined in of the of downstream that be in the our data a role for kinase in Beyond its in Type S. S. K. K. T. R. R. Platanias L.C. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar) and II IFN Mnk activity is essential for mRNA of the gene for M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google a cytokine that exhibits potent effects S. R. J. Immunol. Google Scholar, A. J. S. J. A. Platanias L.C. 2005; PubMed Scopus Google Scholar). Thus, it is as is the for A. A. S. A. S. M. K. Platanias L.C. J. Immunol. 2002; PubMed Scopus Google Scholar, S. Platanias L.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. S. J. A. Platanias L.C. 2005; PubMed Scopus Google Scholar, L.C. PubMed Scopus Google Scholar, L.C. PubMed Scopus Google Mnk is a of signals for the generation of responses in the of to be it the of studies to pathway for the treatment of of PubMed Scopus Google and be in IntroductionThe only known member of the Type II IFN family, IFNγ, plays an important role in the innate and adaptive immunity against microbial and viral infections and exhibits potent antitumor effects (1Isaacs A. Lindenmann J. Proc. R. Soc. Lond. B Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar, 2Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2249) Google Scholar, 3Borden E.C. Sen G.C. Uze G. Silverman R.H. Ransohoff R.M. Foster G.R. Stark G.R. Nat. Rev. Drug. Discov. 2007; 6: 975-990Crossref PubMed Scopus (859) Google Scholar, 4Schoenborn J.R. Wilson C.B. Adv. Immunol. 2007; 96: 41-101Crossref PubMed Scopus (1165) Google Scholar). IFNγ is a cytokine mainly secreted by T lymphocytes, activated natural killer cells, and antigen-presenting cells such as macrophages and dendritic cells (5Schroder K. Hertzog P.J. Ravasi T. Hume D.A. J. Leukocyte Biol. 2004; 75: 163-189Crossref PubMed Scopus (2847) Google Scholar, 6Boehm U. Klamp T. Groot M. Howard J.C. Annu. Rev. Immunol. 1997; 15: 749-795Crossref PubMed Scopus (2462) Google Scholar) and is known to elicit pleiotropic biological effects on cells and tissues. This cytokine enhances the activity of natural killer cells, facilitates class switching, and regulates immunoglobulin production by B cells (5Schroder K. Hertzog P.J. Ravasi T. Hume D.A. J. Leukocyte Biol. 2004; 75: 163-189Crossref PubMed Scopus (2847) Google Scholar, 6Boehm U. Klamp T. Groot M. Howard J.C. Annu. Rev. Immunol. 1997; 15: 749-795Crossref PubMed Scopus (2462) Google Scholar, 7Saha B. Jyothi Prasanna S. Chandrasekar B. Nandi D. Cytokine. 2010; 50: 1-14Crossref PubMed Scopus (226) Google Scholar). In addition, it regulates survival and proliferation of T cells, modulates the activity of antigen presenting cells and, under certain circumstances, can promote differentiation of several distinct cell types (5Schroder K. Hertzog P.J. Ravasi T. Hume D.A. J. Leukocyte Biol. 2004; 75: 163-189Crossref PubMed Scopus (2847) Google Scholar, 6Boehm U. Klamp T. Groot M. Howard J.C. Annu. Rev. Immunol. 1997; 15: 749-795Crossref PubMed Scopus (2462) Google Scholar, 7Saha B. Jyothi Prasanna S. Chandrasekar B. Nandi D. Cytokine. 2010; 50: 1-14Crossref PubMed Scopus (226) Google Scholar). Importantly, IFNγ facilitates immune responses to tumor cells, although it also inhibits angiogenesis and exerts direct anti-proliferative effects on a number of tumor cells (8Ikeda H. Old L.J. Schreiber R.D. Cytokine Growth Factor Rev. 2002; 13: 95-109Crossref PubMed Scopus (668) Google Scholar). Thus, considering the broad effects of IFNγ, understanding the cellular mechanisms that regulate its biological effects is highly relevant in advancing our overall understanding of the mechanisms of innate immunity against cancer and viral infections.Previous studies have established that IFNγ transduces signals by binding to its cell surface receptor, which is composed of two distinct subunits; the IFNγ receptor 1 and 2 chains, which are constitutively associated with the JAK family members JAK1 and JAK2 (reviewed in Refs. 2Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2249) Google Scholar and 3Borden E.C. Sen G.C. Uze G. Silverman R.H. Ransohoff R.M. Foster G.R. Stark G.R. Nat. Rev. Drug. Discov. 2007; 6: 975-990Crossref PubMed Scopus (859) Google Scholar). Binding of IFNγ to its receptor results in interactions between the receptor chains leading to the phosphorylation of the STAT1 transcriptional activator, followed by its dimerization, translocation to the nucleus, and activation of gene transcription by IFNγ-activated sequences (GAS) 2The abbreviations used are: GAS, IFNγ-activated sequences; MEF, mouse embryonic fibroblast; CFU-GM, colony forming unit-granulocyte monocyte; BFU-E, burst forming unit-erythroid. (2Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2249) Google Scholar, 3Borden E.C. Sen G.C. Uze G. Silverman R.H. Ransohoff R.M. Foster G.R. Stark G.R. Nat. Rev. Drug. Discov. 2007; 6: 975-990Crossref PubMed Scopus (859) Google Scholar). Beyond the classic JAK-STAT pathway, the transcriptional response to IFNγ also involves IFNγ-activated transcription elements (9Weihua X. Kolla V. Kalvakolanu D.V. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 103-108Crossref PubMed Scopus (56) Google Scholar) that are controlled by the transcription factor CCAAT enhancer-binding protein-β. Notably, the activity of CCAAT enhancer-binding protein-β is positively regulated by the MAP kinases Erk1 and Erk2 (10Hu J. Roy S.K. Shapiro P.S. Rodig S.R. Reddy S.P. Platanias L.C. Schreiber R.D. Kalvakolanu D.V. J. Biol. Chem. 2001; 276: 287-297Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). There has also protein kinase in the generation of cellular responses to regulates transcriptional by IFNγ J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Stark G.R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google the pathway plays an important role downstream of mRNA of S. A. B. S. B. Platanias L.C. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, S. A. B. M. Platanias L.C. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). family members and have also to important roles in IFNγ J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. B. H. A. Platanias L.C. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, A. B. A. S. S. A. Platanias L.C. J. Immunol. PubMed Scopus Google Scholar). is for important roles for in the induction of IFNγ responses A. A. S. A. S. M. K. Platanias L.C. J. Immunol. 2002; PubMed Scopus Google Scholar, M. A. D. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S.K. J. Shapiro P.S. Reddy S.P. Platanias L.C. G. J. Kalvakolanu D.V. Proc. Natl. Acad. Sci. U.S.A. 2002; PubMed Scopus Google Scholar, S. M. J. PubMed Scopus Google (MAPK-interacting protein 1 and 2 are activated engagement of the Type II IFN receptor and in the generation of IFNγ responses. Mnk1 is a downstream for the and and with the regulates phosphorylation of eIF4E R. T. J. 1997; PubMed Scopus Google Scholar, A. J. 1997; PubMed Scopus Google Scholar). Our data that IFNγ treatment results in activation of Mnk1 and its downstream eIF4E in an In studies cells, we found that Mnk activity is essential for mRNA of IRF-1 regulatory factor 1) and plays a role in the generation of responses by the Type II IFN our findings identify Mnk1 as a for mRNA of and generation of IFNγ antiproliferative responses.

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