The Role of Mitogen-activated Protein Kinase Phosphatase-1 in the Response of Alveolar Macrophages to Lipopolysaccharide

Mitogen-activated protein (MAP) kinases are critical mediators of innate immune responses. In response to lipopolysaccharide (LPS), MAP kinases are rapidly activated and play an important role in the production of proinflammatory cytokines. Although a number of MAP kinase phosphatases (MKPs) have been identified, their roles in the control of cytokine production have not been well defined. In the present report, we investigated the role of MKP-1 in alveolar macrophages stimulated with LPS. We found that LPS triggered transient activation of three MAP kinase subfamilies, ERK, JNK, and p38, in both immortalized and primary murine alveolar macrophages. MKP-1 was rapidly induced by LPS, and its induction correlated with the dephosphorylation of these MAP kinases. Blocking MKP-1 with triptolide prolonged the activities of both JNK and p38 in immortalized alveolar macrophages. Stimulation of primary alveolar macrophages isolated from MKP-1-deficient mice with LPS resulted in a prolonged p38 phosphorylation compared with wild type alveolar macrophages. Accordingly, these MKP-1-deficient alveolar macrophages also mounted a more robust and rapid tumor necrosis factor α production than their wild type counterparts. Adenovirus-mediated MKP-1 overexpression significantly attenuated tumor necrosis factor α production in immortalized alveolar macrophages. Finally, MKP-1 was induced by a group of corticosteroids frequently prescribed for the treatment of inflammatory lung diseases, and the anti-inflammatory potencies of these drugs closely correlated with their abilities to induce MKP-1. Our studies indicated that MKP-1 plays an important role in dampening the inflammatory responses of alveolar macrophages. We speculate that MKP-1 may represent a novel target for therapeutic intervention of inflammatory lung diseases. Mitogen-activated protein (MAP) kinases are critical mediators of innate immune responses. In response to lipopolysaccharide (LPS), MAP kinases are rapidly activated and play an important role in the production of proinflammatory cytokines. Although a number of MAP kinase phosphatases (MKPs) have been identified, their roles in the control of cytokine production have not been well defined. In the present report, we investigated the role of MKP-1 in alveolar macrophages stimulated with LPS. We found that LPS triggered transient activation of three MAP kinase subfamilies, ERK, JNK, and p38, in both immortalized and primary murine alveolar macrophages. MKP-1 was rapidly induced by LPS, and its induction correlated with the dephosphorylation of these MAP kinases. Blocking MKP-1 with triptolide prolonged the activities of both JNK and p38 in immortalized alveolar macrophages. Stimulation of primary alveolar macrophages isolated from MKP-1-deficient mice with LPS resulted in a prolonged p38 phosphorylation compared with wild type alveolar macrophages. Accordingly, these MKP-1-deficient alveolar macrophages also mounted a more robust and rapid tumor necrosis factor α production than their wild type counterparts. Adenovirus-mediated MKP-1 overexpression significantly attenuated tumor necrosis factor α production in immortalized alveolar macrophages. Finally, MKP-1 was induced by a group of corticosteroids frequently prescribed for the treatment of inflammatory lung diseases, and the anti-inflammatory potencies of these drugs closely correlated with their abilities to induce MKP-1. Our studies indicated that MKP-1 plays an important role in dampening the inflammatory responses of alveolar macrophages. We speculate that MKP-1 may represent a novel target for therapeutic intervention of inflammatory lung diseases. Bacterial pneumonia represents a serious challenge to the public health. In the United States alone, ∼4 to 5 million cases of community-acquired pneumonia occur each year, accounting for 10 million physician visits, a half million hospitalizations, and ∼45,000 deaths (1Bartlett J.G. Breiman R.F. Mandell L.A. File Jr., T.M. Clin. Infect. Dis. 1998; 26: 811-838Crossref PubMed Scopus (857) Google Scholar). Among cases of the community-acquired pneumonia, ∼10% are caused by Gram-negative bacteria. Nosocomial pneumonia, which is primarily caused by Gram-negative bacteria and has a mortality rate of up to 30%, accounts for about 15% of all hospital-acquired infections (2Septimus E.J. Semin. Respir. Infect. 1989; 4: 245-252PubMed Google Scholar). Thus, elucidation of the pulmonary immune responses to Gram-negative bacteria is crucial for the development of therapeutic strategies to prevent and alleviate lung injury. Alveolar macrophages constitute the first line of immune defense against microbial agents that infiltrate the gas-exchanging airways (3File T.M. Semin. Respir. Infect. 2000; 15: 184-194Crossref PubMed Scopus (61) Google Scholar, 4Zhang P. Summer W.R. Bagby G.J. Nelson S. Immunol. Rev. 2000; 173: 39-51Crossref PubMed Scopus (333) Google Scholar). These cells serve important phagocytic, microbicidal, and secretory functions and play a prominent role in lung immunity by initiating inflammatory and immune responses. Alveolar macrophages are essential for the daily clearance of air-borne microbial infiltration and maintaining the sterility of the delicate alveolar surfaces for effective gas exchange. When invading pathogens overwhelm the innate host defenses and establish an infection in the lung, as in bacterial pneumonia, alveolar macrophages are capable of initiating profound inflammatory responses. As a critical part of the innate immune defense, alveolar macrophages produce an array of inflammatory mediators that orchestrate the recruitment of polymorphonuclear leukocytes from the pulmonary vasculature into the alveolar spaces for the effective eradication of the offending pathogens (5Sibille Y. Reynolds H.Y. Am. Rev. Respir. Dis. 1990; 141: 471-501Crossref PubMed Scopus (923) Google Scholar). Among the crucial inflammatory mediators produced by alveolar macrophages are proinflammatory cytokines, including tumor necrosis factor (TNF) 1The abbreviations used are: TNF, tumor necrosis factor; LPS, lipopolysaccharide; MAP, mitogen-activated protein; MKP, MAP kinase phosphatase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; DAPI, 4,6-diamidino-2-phenylindole; m.o.i., multiplicity/multiplicities of infection; TBS, Tris-buffered saline; GST, glutathione S-transferase.1The abbreviations used are: TNF, tumor necrosis factor; LPS, lipopolysaccharide; MAP, mitogen-activated protein; MKP, MAP kinase phosphatase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; DAPI, 4,6-diamidino-2-phenylindole; m.o.i., multiplicity/multiplicities of infection; TBS, Tris-buffered saline; GST, glutathione S-transferase.-α, interleukin 1β, and interleukin 6. Although these inflammatory cytokines are beneficial to pulmonary host defense, excessive production of these cytokines is involved in the pathogenesis of inflammatory lung injury, which can result in failure of lung function in severe cases (6Mizgerd J.P. Spieker M.R. Doerschuk C.M. J. Immunol. 2001; 166: 4042-4048Crossref PubMed Scopus (114) Google Scholar). Macrophage activation and the subsequent production of proinflammatory cytokines as responses to Gram-negative bacteria have been studied extensively (7Beutler B. Kruys V. J. Cardiovasc. Pharmacol. 1995; 25: S1-S8Crossref PubMed Scopus (93) Google Scholar). Lipopolysaccharide (LPS), a cell wall component unique to Gram-negative bacteria, forms complexes with the LPS-binding protein. These complexes then interact with CD14 and toll-like receptor-4, leading to the activation of a multitude of signaling cascades that ultimately result in the biosynthesis of a group of proinflammatory cytokines (7Beutler B. Kruys V. J. Cardiovasc. Pharmacol. 1995; 25: S1-S8Crossref PubMed Scopus (93) Google Scholar, 8Ono K. Han J. Cell. Signal. 2000; 12: 1-13Crossref PubMed Scopus (1372) Google Scholar). MAP kinases, including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38, play crucial roles in this process. Carter et al. (9Carter A.B. Monick M.M. Hunninghake G.W. Am. J. Respir. Cell Mol. Biol. 1999; 20: 751-758Crossref PubMed Scopus (280) Google Scholar) have demonstrated that, in LPS-stimulated human alveolar macrophages, both p38 and ERK are required for the maximal production of TNF-α and interleukin-6. It has been reported that JNK is potently activated in response to LPS stimulation in primary rat alveolar macrophages (10Zhang P. Nelson S. Holmes M.C. Summer W.R. Bagby G.J. Shock. 2002; 17: 104-108Crossref PubMed Scopus (25) Google Scholar), although the role of JNK in the macrophage responses to LPS has not been defined. Also poorly understood are the negative regulation of MAP kinases in alveolar macrophages and the mechanisms responsible for the termination of the biosynthesis of proinflammatory cytokines. In the present report, we examined the function and regulation of MAP kinase phosphatase (MKP)-1 in LPS-stimulated primary and immortalized alveolar macrophages. We found that MKP-1 is highly induced by LPS in alveolar macrophages, and its induction is associated with the inactivation of MAP kinases. Using primary alveolar macrophages isolated from MKP-1-deficient mice, we demonstrated that MKP-1 acts in vivo to attenuate the p38 MAP kinase cascade, thus inhibiting the biosynthesis of proinflammatory cytokines. We also found that MKP-1 is highly induced by a group of corticosteroids commonly prescribed for the treatment of inflammatory lung diseases. Moreover, the abilities of these corticosteroids to induce MKP-1 are correlated with their relative anti-inflammatory potencies. Our studies suggested that MKP-1 plays an important role in the pulmonary innate immune defense and could be a novel target for the development of new anti-inflammatory drugs. Animals—Male C57BL/6 mice (8–12 weeks old) were purchased from Harlan Sprague-Dawley (Indianapolis, IN). The generation of MKP-1 knock-out mice has been described previously (11Dorfman K. Carrasco D. Gruda M. Ryan C. Lira S.A. Bravo R. Oncogene. 1996; 13: 925-931PubMed Google Scholar). Cryopreserved embryos of MKP-1 knock-out mice (MKP-1+/- and MKP-1-/-) were kindly provided by Bristol-Myers Squibb Co. and were regenerated into mice in The Jackson Laboratory (Bar Harbor, ME). These mice were bred in-house to yield both wild type and MKP-1-/- mice. All of the mice were maintained on Harlan Tecklad irradiated diet (Harlan) at 24 °C with relative humidity between 30 and 70% on a 12-h day-night cycle. All of the animals received humane care in accordance with the guidelines of the National Institutes of Health and were sacrificed by CO2 inhalation. The experimental protocols were approved by the Institutional Animal Care and Use Committee of the Columbus Children's Research Institute. Isolation of Primary Murine Alveolar and Peritoneal Macrophages, Cell Culture, and Treatment—Resident bronchoalveolar macrophages were isolated from naive male C57BL/6, MKP-1+/+, or MKP-1-/- mice by alveolar lavage. Briefly, murine lungs were filled and flushed 15–20 times with 0.7 ml of prewarmed phosphate-buffered saline supplemented with 5 mm EDTA. This procedure yielded about 10 ml of lung lavage per animal. Cells in the alveolar lavage were collected by centrifugation at 800 × g for 8 min at 4 °C and plated into tissue culture dishes in RPMI 1640 (Mediatech, Herndon, VA) supplemented with 10% fetal bovine serum (Hyclone Laboratories, Logan, UT) and 2 mm l-glutamine. For immunofluorescence the alveolar macrophages were For the role of MKP-1 in TNF-α cell × alveolar macrophages, with were plated into tissue culture cells were by with phosphate-buffered The macrophages were in stimulated with LPS cells were into and culture collected as described previously P. J. J. Y. J. Immunol. 2002; PubMed Scopus Google Scholar). macrophages were isolated from naive male or MKP-1-/- mice by a lavage of the three times each with 4 ml of Cells in the lavage were collected by centrifugation at 800 × g for 8 min at 4 °C and were plated in RPMI 1640 supplemented with fetal bovine serum and 2 mm l-glutamine. cells were by with phosphate-buffered The macrophages were in supplemented with stimulated with LPS alveolar macrophage cells were purchased from VA) and were in 10% fetal bovine 2 mm 10 mm mm and at °C in a LPS was to the cell culture to a of in was to the at indicated 30 min the cells with LPS. and all purchased from were in as 5 mm and were to the to a of 5 MKP-1 has been described previously D. M. J. Biol. PubMed Scopus Google Scholar). was kindly provided by of the of was and in were with fetal bovine The cells were with in of fetal bovine serum for on a at °C in a was to the cells were with and were to stimulation with LPS. and was as described previously P. J. J. Y. J. Immunol. 2002; PubMed Scopus Google Scholar). MKP-1 was a purchased from JNK, p38, and ERK were purchased from Cell p38 or in the cell were an against p38 or TNF-α in the culture was the to the the phosphorylation of p38 in alveolar macrophages cells were first in for min at 4 °C and then were with Tris-buffered saline 10% serum and bovine serum at for the cells were at 4 °C with a or at a of The cells were with and with for then were with an for at times with the cells were with to the and were examined a The were with for all of the The was The of cells were as the and were from the of at and was isolated was a MKP-1 as a as described previously P. J. J. Y. J. Immunol. 2002; PubMed Scopus Google Scholar, J. M. D. J. Y. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). The was and with to for For was isolated from to J. Laboratory Harbor, Scholar). of the was with was the MKP-1 as a as described previously Y. S. M. R. K. S. Mol. PubMed Scopus Google Scholar). was by immune kinase as described previously Y. M. C. J. Biol. 1995; PubMed Scopus Google Scholar, D. P. J. Y. J. 2000; PubMed Scopus Google Scholar, P. D. P. Y. 2002; PubMed Scopus Google Scholar), and as a P. J. PubMed Scopus Google Scholar). The of into the was a and the between MKP-1 and of MAP in LPS-stimulated Alveolar the regulation of MAP kinases in alveolar macrophages, we stimulated immortalized murine alveolar macrophage cells with LPS for of The activation of ERK and p38 MAP kinases in the cells were by In control alveolar macrophages, p38 was LPS p38 was rapidly maximal at about then p38 to The in p38 was to p38 not the of the ERK was also potently activated in response to LPS stimulation with to that of p38 The of LPS on was examined by immune kinase as a to was for p38, was also activated in response to LPS, maximal at min and to line 2 The of in protein that activation was also to phosphorylation It has been that in inactivation of MAP kinases is primarily by a group of MAP kinase phosphatases Cell Biol. 2000; 12: PubMed Scopus Google Scholar). We have found that LPS the of MKP-1 in cells P. J. J. Y. J. Immunol. 2002; PubMed Scopus Google Scholar). MKP-1 plays a role in the regulation of MAP kinases in alveolar macrophages, we investigated the of LPS on MKP-1 MKP-1 was examined with alveolar macrophages of MKP-1 LPS MKP-1 were rapidly The in MKP-1 was MKP-1 were at about by a the in MKP-1 MKP-1 protein were also LPS stimulation MKP-1 protein was 30 and its were significantly by MKP-1 protein were at about Although MKP-1 to by min MKP-1 protein was an against a The between MKP-1 induction and the inactivation of MAP kinases that MKP-1 plays a role in the dephosphorylation of these MAP kinases. the between MKP-1 and MAP kinases, we used triptolide to the induction of MKP-1 and examined the of this MKP-1 on the activation of MAP kinases LPS of cells with triptolide not an on the MKP-1 attenuated MKP-1 in a with the that MKP-1 plays an important role in the dephosphorylation of MAP kinases, the of MKP-1 induction by triptolide the dephosphorylation of p38 and JNK and In triptolide on the dephosphorylation of ERK the responses of alveolar macrophages to LPS, as indicated by the activation of p38 in the of triptolide These that triptolide not the of that MKP-1 was responsible for the prolonged activation of p38 and JNK in LPS-stimulated MKP-1 plays a role in the responses of primary alveolar macrophages to LPS, we studied MAP kinase regulation bronchoalveolar macrophages isolated from naive male C57BL/6 mice. We found that of alveolar macrophages from the lungs by lavage was yielded × alveolar macrophages. the in of primary alveolar macrophages, we immunofluorescence to the activation of p38 in LPS-stimulated primary alveolar macrophages, a for p38 In alveolar macrophages, of were LPS were with maximal at about 30 which was by a in It is that at min the in the cells to the in the responses of of the in as a of indicated that p38 by and by 2 p38 to in both the and which were by the of the p38 we to the activation of p38 LPS stimulation C57BL/6 mice, × alveolar macrophages were collected and to was with the immunofluorescence LPS stimulation resulted in a transient activation of p38, with maximal phosphorylation between and 30 the p38 rapidly by JNK and ERK also a transient activation with to of p38 activation with the inactivation of these MAP kinases, MKP-1 a induction LPS stimulation MKP-1 protein by 30 min and by of in cells the by the of immunofluorescence for the of in LPS-stimulated alveolar macrophages. these that MKP-1 is a of MAP kinases in alveolar macrophages bacterial of MKP-1 on p38 and TNF-α in Alveolar the functions of we embryos of MKP-1 knock-out mice from Bristol-Myers Squibb and regenerated these embryos into mice. The MKP-1 mice were bred to produce wild type and The of these were by the of MKP-1 protein in the MKP-1 knock-out mice, macrophages were isolated from wild type and MKP-1-/- mice and with Stimulation of the macrophages with LPS for min resulted in a in MKP-1 protein in wild type not in MKP-1-/- the of MKP-1 function in these animals compared with the macrophages, the MKP-1-/- macrophages significantly of and a crucial role for MKP-1 in the dephosphorylation of these kinases in these cells of the of alveolar macrophages isolated from mice, the of p38 activation in wild type and MKP-1-deficient alveolar macrophages were examined by immunofluorescence an for In wild type alveolar macrophages, LPS resulted in a transient p38 phosphorylation that its maximal at min and to by LPS also triggered a rapid p38 phosphorylation in MKP-1-deficient the rapid dephosphorylation of p38 in wild type alveolar macrophages, p38 for a in MKP-1-deficient alveolar macrophages. In the of p38 phosphorylation at and min not from the These that MKP-1 plays a critical role in the negative control of p38 in LPS-stimulated alveolar macrophages. the function of MKP-1 in the regulation of TNF-α alveolar macrophages isolated from both wild type and the MKP-1-deficient mice were stimulated with LPS for 4 and and the was TNF-α in the were by with the wild type alveolar macrophages, the MKP-1-deficient cells produced significantly more TNF-α at both the and Our that MKP-1-deficient alveolar macrophages were to a more robust and rapid inflammatory responses than were wild type the function of MKP-1 in the regulation of proinflammatory cytokines in alveolar macrophages, we examined the of MKP-1 overexpression on TNF-α production in alveolar macrophages. cells were to was to MKP-1 cells were with or at of or 800 of infection cells were stimulated with LPS for 4 or TNF-α into the was by of cells with the not the resulted in a of TNF-α with 800 of MKP-1 resulted in a in TNF-α infection with the of These that of MKP-1 TNF-α these that MKP-1 plays an important role in the responses of alveolar macrophages to LPS to prevent of proinflammatory cytokines. of MKP-1 by are anti-inflammatory drugs frequently prescribed to inflammatory lung diseases, including J. 1995; PubMed Scopus Google Scholar), pulmonary and J. 1995; PubMed Scopus Google Scholar). the production of inflammatory cytokines triggered by LPS J. Biol. 1996; PubMed Scopus Google Scholar). as have been to JNK, p38, and ERK activation in cell Mol. Cell. Biol. 17: PubMed Google Scholar, M. C. J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, D. M. 1999; PubMed Scopus Google Scholar). studies have that MKP-1 is induced by in a number of cell including macrophages, and cells P. J. J. Y. J. Immunol. 2002; PubMed Scopus Google Scholar, M. C. J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, J. B. M. J. 2001; 20: PubMed Scopus Google Scholar). the between the potencies of anti-inflammatory and their abilities to induce we examined the induction of MKP-1 in alveolar macrophages by commonly prescribed anti-inflammatory and cells were with each of the corticosteroids at a of 5 for 8 and MKP-1 was then examined by All corticosteroids the of although to Moreover, corticosteroids induced MKP-1 to a than the drugs. For to anti-inflammatory is as P. J. of B. Scholar) and anti-inflammatory P. J. of B. Scholar) resulted in a induction of MKP-1 than anti-inflammatory P. J. of B. Scholar) and anti-inflammatory P. J. of B. Scholar). Although the of the relative anti-inflammatory potencies for the corticosteroids are also that MKP-1 induction correlated with anti-inflammatory potencies. It has been reported that the relative anti-inflammatory of the corticosteroids in an of 1998; PubMed Scopus Google Scholar). Although of the with drugs are is by to be a highly anti-inflammatory Thus, the the that MKP-1 may play a role in the anti-inflammatory of MAP kinase play an important role in the immune responses to microbial infection C. Rev. Immunol. 2002; 20: PubMed Scopus Google Scholar). In macrophages, MAP kinases are crucial of the production of proinflammatory cytokines in response to bacterial the MAP kinases are dephosphorylation by a of Cell Biol. 2000; 12: PubMed Scopus Google Scholar), is that these phosphatases may play a role in the negative control of cytokine In this report, we have examined the role of an MKP, in the innate immune responses of alveolar macrophages to LPS, a of Gram-negative bacterial We found that in both immortalized and primary alveolar macrophages, MKP-1 was highly induced by LPS, and this induction correlated with dephosphorylation of all three MAP kinases, including ERK, JNK, and p38 and MKP-1 not and attenuated the in MKP-1 protein. It also the inactivation of JNK and p38 Adenovirus-mediated overexpression of MKP-1 in the immortalized alveolar macrophages significantly attenuated the production of the of MKP-1 to the MAP kinase cascades and the production of proinflammatory cytokines we found that the dephosphorylation of p38 that the activation LPS treatment was significantly in MKP-1-deficient alveolar macrophages compared with their wild type Moreover, MKP-1-deficient cells were to a more robust and rapid production of TNF-α than were wild type cells in response to LPS These that MKP-1 may play a role in the negative control of p38 in alveolar macrophages LPS Our studies to a role for MKP-1 in the production of inflammatory cytokines by the innate immune cells pulmonary In MKP-1 is capable of all three MAP kinase subfamilies, including ERK, JNK, and p38 Y. M. C. J. Biol. 1995; PubMed Scopus Google Scholar, Cell. PubMed Scopus Google Scholar, J. S. M. Han J. J. Biol. 1995; PubMed Scopus Google Scholar). studies have suggested that MKP-1 p38 and JNK as J. Biol. PubMed Scopus Google Scholar). This is with a that of the MKP-1 not significantly the activation of ERK in (11Dorfman K. Carrasco D. Gruda M. Ryan C. Lira S.A. Bravo R. Oncogene. 1996; 13: 925-931PubMed Google Scholar). We found that in macrophages, MKP-1 to all three MAP kinase MKP-1-deficient macrophages phosphorylation for all three MAP kinases than wild type cells LPS stimulation It as to MKP-1 plays a critical role in the dephosphorylation of all three MAP kinase in alveolar macrophages. In alveolar macrophages, of MKP-1 by triptolide on ERK that ERK is not a target of MKP-1 in this cell with the immortalized alveolar macrophages than to this although triptolide the induction of the MKP-1 as indicated by not triptolide not prevent the in MKP-1 protein LPS stimulation which is to the in MKP-1 protein P. J. J. Y. J. Immunol. 2002; PubMed Scopus Google Scholar, J. 1999; PubMed Scopus Google Scholar). alveolar macrophages are to the of these and of alveolar macrophages have the regulation of critical these we of the MKP-1 knock-out mice and studied the function of MKP-1 in primary alveolar macrophages. primary alveolar macrophages unique to the relative of alveolar macrophages in mice and the of MKP-1 knock-out we immunofluorescence to MAP kinase activities between primary alveolar macrophages from wild type and from MKP-1-deficient mice. We found that of both and in a alveolar macrophages yielded to by the of for these kinases we provided a critical role of MKP-1 in the negative control of p38 in LPS-stimulated alveolar macrophages of has not an in ERK in LPS-stimulated MKP-1-deficient alveolar macrophages not we have been to an that is for We to the role of MKP-1 in the regulation of JNK and ERK in LPS-stimulated alveolar macrophages in the important and in this is the of the relative anti-inflammatory potencies of corticosteroids with their to induce MKP-1 As effective anti-inflammatory corticosteroids are used to inflammatory lung diseases. has been to the activities of MAP kinases Mol. Cell. Biol. 17: PubMed Google Scholar, M. C. J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, J. B. M. J. 2001; 20: PubMed Scopus Google Scholar) and to the production of inflammatory cytokines J. Biol. 1996; PubMed Scopus Google Scholar). We have previously demonstrated that MKP-1 is potently induced by in macrophages P. J. J. Y. J. Immunol. 2002; PubMed Scopus Google Scholar). In this report, we studied corticosteroids commonly prescribed for the treatment of inflammatory lung and found a between the relative anti-inflammatory potencies of these and the to induce MKP-1 at a This is that the anti-inflammatory potencies of the are by both the of the drugs and the of the drugs the These that induction of MKP-1 may to the therapeutic of these drugs. We speculate that of MKP-1 bacterial infection may in part be responsible for the inflammatory response in lung diseases, as and MKP-1 may represent a novel therapeutic target for inflammatory lung diseases. We and for kindly with We are to Bristol-Myers Squibb Research for mice.