Endotoxin induced myocardial dysfunction : effects of macrophage migration inhibitory factor neutralization. (2005 May)
endotoxin induced myocardial dysfunction : effects of macrophage migration inhibitory factor neutralization . The pathophysiology of sepsis induced myocardial dysfunction still remains controversial . macrophage migration inhibitory factor ( MIF ) has recently been identified as a cardiac derived myocardial depressant factor in septic shock . putative mechanisms by which MIF affects cardiac function are unknown . In an investigation of possible mechanisms of action , a rat model of endotoxin toxicity was designed using intraperitoneal ( I / P ) injection of lipopolysaccharides ( LPS ) with or without coinfusion of neutralizing anti MIF or isotypic matched antibodies . echocardiographic evaluation revealed that MIF neutralization reversed endotoxin induced myocardial dysfunction at 24 hours after injection . rnase protection assay ( RPA ) and western blot established that MIF neutralization prevented LPS induced mRNA expression and production of heart derived inflammatory paracrine and autocrine cytokines such as IL 1s and IL 6 . moreover , MIF immunoneutralization increased heart Bcl 2 / Bax protein ratio and suppressed endotoxin induced release of mitochondrial cytochrome c , as demonstrated by western blotting . inhibition of mitochondrial loss of cytochrome c decreased in heart caspase 3 activity at 6 and 24 hours after injection . MIF neutralization also restored the LPS induced deficient nuclear translocation of phospho Akt and consequently the expression of the heart survival nuclear factor GATA 4 . The restoration of the translocation / expression of survival factors by MIF inhibition resulted in lowered endotoxin induced DNA fragmentation at 24 …

Corticoids normalize leukocyte production of macrophage migration inhibitory factor in septic shock. (2004 Dec)
corticoids normalize leukocyte production of macrophage migration inhibitory factor in septic shock . background : A regulatory loop between macrophage migration inhibitory factor ( MIF ) and glucocorticoids has been characterized in animal models . renewed interest in glucocorticoid treatment for septic shock offers an opportunity to analyze this regulatory loop in humans . methods : We investigated the ex vivo release of MIF by peripheral blood mononuclear cells ( pbmcs ) sampled from glucocorticoid treated and untreated patients with septic shock . blood was obtained , before glucocorticoid treatment , and within the first day of treatment , from patients with septic shock who required treatment with moderate doses of hydrocortisone and fludrocortisone . results : pbmcs from patients contained significantly higher amounts of MIF than cells from healthy control subjects . In culture , spontaneous release of MIF and release induced by lipopolysaccharide ( LPS ) , heat killed staphylococci , and red blood cell lysates were significantly higher in patients than in control subjects . pbmcs from patients treated with glucocorticoids showed a lower release of MIF in response to LPS , heat killed escherichia coli , and peptidoglycan than did pbmcs from untreated patients and showed levels similar to pbmcs from healthy control subjects . conclusion : To our knowledge , MIF is the first proinflammatory cytokine in which ex vivo release by circulating cells is enhanced during sepsis . glucocorticoid treatment normalized the release of MIF by circulating pbmcs from patients with septic shock .

MIF regulates innate immune responses through modulation of Toll like receptor 4. (2002 Jan)
MIF regulates innate immune responses through modulation of Toll like receptor 4 . macrophages are pivotal effector cells of the innate immune system , which is vital for recognizing and eliminating invasive microbial pathogens . When microbial products bind to pathogen recognition receptors , macrophages become activated and release a broad array of cytokines that orchestrate the host innate and adaptive immune responses . initially identified as a T cell cytokine , macrophage migration inhibitory factor ( MIF ) is also a macrophage cytokine and an important mediator of inflammation and sepsis . Here we report that MIF is an essential regulator of macrophage responses to endotoxin ( lipopolysaccharide ) and Gram negative bacteria . compared with wild type cells , MIF deficient macrophages are hyporesponsive to lipopolysaccharide and Gram negative bacteria , as shown by a profound reduction in the activity of NF kappab and the production of tumour necrosis factor alpha . This reduction is due to a downregulation of Toll like receptor 4 ( TLR4 ) , the signal transducing molecule of the lipopolysaccharide receptor complex , and is associated with decreased activity of transcription factor PU . 1 , which is required for optimal expression of the Tlr4 gene in myeloid cells . these findings identify an important role for MIF in innate immunity and provide a molecular basis for the resistance of MIF deficient mice to endotoxic shock .

Plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis. (2001 Aug)
plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis . objective : To investigate the role of macrophage migration inhibitory factor ( MIF ) as a marker of severity of systemic inflammation in patients with severe sepsis and critically ill postsurgical patients . design : prospective observational study in consecutive patients with severe sepsis , critically ill nonseptic postsurgical patients , and healthy blood donors . setting : A surgical intensive care unit of a university hospital . patients AND participants : 19 patients with severe sepsis , 18 critically ill nonseptic postsurgical patients , and 10 healthy blood donors . measurements AND results : MIF plasma levels of patients and participants were measured . interleukin 6 plasma levels were monitored as a control marker of inflammation . The median MIF plasma level was four to five times higher in patients with severe sepsis ( 2 . 70 ng / ml , range 0 . 31 19 . 59 ) and in critically ill nonseptic postsurgical patients ( 2 . 43 ng / ml , range 0 . 49 4 . 31 ) than in healthy blood donors ( 0 . 56 ng / ml , range 0 . 16 1 . 68 ) . MIF plasma levels did not differ between the patient groups . conclusions : MIF serves as a general marker for systemic inflammation in septic and nonseptic acute critical illness , but MIF does not discriminate for severity or differentiate between …

Macrophage migration inhibitory factor is a cardiac derived myocardial depressant factor. (2003 Nov)
macrophage migration inhibitory factor is a cardiac derived myocardial depressant factor . macrophage migration inhibitory factor ( MIF ) is a pluripotent proinflammatory cytokine that is ubiquitously expressed in organs , including the heart . however , no specific role for MIF in modulating cardiac performance has yet been described . therefore , we examined cardiac MIF expression in mice after LPS challenge ( 4 mg / kg ) and tested the hypothesis that MIF is a mediator of LPS induced cardiac dysfunction . western blots of whole heart lysates , as well as immunohistochemistry , documented constitutive MIF protein expression in the heart . cardiac MIF protein levels significantly decreased after LPS challenge , reaching a nadir at 12 h , and then returned to baseline by 24 h . This pattern was consistent with MIF release from cytoplasmic stores after endotoxin challenge . after release of protein , MIF mRNA levels increased 24 48 h postchallenge . To determine the functional consequences of MIF release , we treated LPS challenged mice with anti MIF neutralizing antibodies or isotype control antibodies . Anti MIF treated animals had significantly improved cardiac function , as evidenced by a significant improvement in left ventricular ( LV ) fractional shortening percentage at 8 , 12 , 24 , and 48 h after endotoxin challenge . In support of these findings , perfusion of isolated beating mouse hearts ( langendorff preparation ) with recombinant MIF ( 20 ng / ml ) led to a …

Development and validation of a multiplex add on assay for sepsis biomarkers using xMAP technology. (2006 Jun)
development and validation of a multiplex add on assay for sepsis biomarkers using xMAP technology . background : sepsis is a common and often fatal disease . because sepsis can be caused by many different organisms , biomarkers that can aid in diagnosing sepsis and monitoring treatment efficacy are highly warranted . New sepsis markers may provide additional information to complement the currently used markers . methods : We used a combination of in house and commercially available multiplex immunoassays based on luminex xMAP technology to assay biomarkers of potential interest in EDTA plasma samples . results : A 3 plex assay for soluble urokinase plasminogen activator receptor ( supar ) , soluble triggering receptor expressed on myeloid cells 1 ( strem 1 ) , and macrophage migration inhibiting factor ( MIF ) was developed and validated in house . This 3 plex assay was added to a commercially available interleukin 1beta ( IL 1beta ) , IL 6 , IL 8 , granulocyte / macrophage colony stimulating factor , and tumor necrosis factor alpha human cytokine panel . No cross reactivity was observed when the assays were combined . correlation between values obtained with the 8 plex , the 5 cytokine panel , the 3 in house 1 plex assays , and a supar elisa ranged from 0 . 86 to 0 . 99 . Mean within and between run CVs were 8 . 0 and 11 , respectively . recoveries of supar , strem 1 , and MIF …

Lung derived macrophage migration inhibitory factor in sepsis induces cardio circulatory depression. (2007 Mar)
Lung derived macrophage migration inhibitory factor in sepsis induces cardio circulatory depression . background : acute lung injury is common during sepsis . whereas gaseous exchange often can be supported adequately , death results frequently from cardio circulatory depression , the mechanisms of which remain unclear . The aim of this study was to determine whether cardio circulatory dysfunction during sepsis results from release of macrophage migration inhibitory factor ( MIF ) by the lung . methods : polymicrobial sepsis was induced by cecal ligation and puncture ( CLP ) in adult sprague dawley rats . macrophage MIF was measured in the plasma sampled from the right ventricle ( pre lung ) and left atrium ( post lung ) . results : The concentration of macrophage MIF in each of the post lung samples was higher than in the corresponding pre lung sample at 6 h ( p 0 . 015 ; paired t test ) , 20 h ( p 0 . 008 ) , and 30 h ( p 0 . 026 ) after the induction of sepsis . Next , rats that underwent CLP were treated with either saline ( control ) or our specific MIF inhibitor , ( S , R ) 3 ( 4 hydroxyphenyl ) 4 , 5 dehydro 5 isoxazole acetic acid methyl ester ( ISO 1 ) . echocardiography revealed that ISO 1 significantly improved the left ventricular end diastolic volume index ( p 0 . 02 ) , stroke volume index …

Glucocorticoid counter regulation : macrophage migration inhibitory factor as a target for drug discovery. (2001 Dec)
glucocorticoid counter regulation : macrophage migration inhibitory factor as a target for drug discovery . Over the past year , human studies have confirmed and expanded the involvement of macrophage migration inhibitory factor ( MIF ) in a number of diseases that had originally been studied in animals . In addition to sepsis , rheumatoid arthritis , glomerulonephritis and inflammatory lung disease , elevated MIF levels have been described in patients suffering from ulcerative colitis , inflammatory neurological diseases and cancer . cellular studies indicate that in addition to macrophages , MIF affects the activities of CD4 and CD8 T cells , natural killer cells , fibroblasts and endothelial cells , actions that may explain the contribution of MIF to inflammatory diseases and cancer . molecular studies have identified direct interactions between MIF and several intracellular regulatory proteins ( Jab1 , PAG and p53 ) that control cellular growth and proliferation ; however , how interactions with these proteins fit into a general scheme to explain MIF s biological activity has not been elucidated . The three dimensional structure of MIF has offered some surprising clues and if the potential enzymatic sites identified are involved with MIF associated diseases , they may provide good targets for therapeutic intervention .

Macrophage migration inhibitory factor : a regulator of innate immunity. (2003 Sep)
macrophage migration inhibitory factor : a regulator of innate immunity . For more than a quarter of a century , macrophage migration inhibitory factor ( MIF ) has been a mysterious cytokine . In recent years , MIF has assumed an important role as a pivotal regulator of innate immunity . MIF is an integral component of the host antimicrobial alarm system and stress response that promotes the pro inflammatory functions of immune cells . A rapidly increasing amount of literature indicates that MIF is implicated in the pathogenesis of sepsis , and inflammatory and autoimmune diseases , suggesting that MIF directed therapies might offer new treatment opportunities for human diseases in the future .

Improved resistance to bacterial superinfection in mice by treatment with macrophage migration inhibitory factor. (2005 Sep)
improved resistance to bacterial superinfection in mice by treatment with macrophage migration inhibitory factor . nosocomial infections in immune suppressed patients are a widespread problem in intensive care medicine . Such patients are highly susceptible to infections because their immune defenses are impaired and , therefore , unable to adequately combat invading microorganisms . To investigate the problem of sepsis induced immune suppression , we used a model in which mice developed sublethal peritonitis induced by cecal ligation and puncture ( CLP ) . Two days after CLP mice were in an immune suppressed state , as measured by impaired capacity to produce tumor necrosis factor ( TNF ) and enhanced susceptibility to bacterial infections . since macrophage migration inhibitory factor ( MIF ) is a critical mediator of septic shock by modulation of innate immune responses , the role of MIF in sepsis induced immune suppression was analyzed . neutralization of endogenous MIF further enhanced susceptibility to bacterial superinfection after CLP . conversely , treatment with recombinant human MIF before the bacterial superinfection protected the animals . MIF treatment reconstituted the impaired capacity to produce proinflammatory cytokines , such as TNF and interleukin 6 . This study indicates that MIF might be able to ameliorate the sepsis induced immune suppression by reenabling the organism to react adequately to a secondary bacterial challenge .

Association between high levels of blood macrophage migration inhibitory factor , inappropriate adrenal response , and early death in patients … (2007 Apr)
association between high levels of blood macrophage migration inhibitory factor , inappropriate adrenal response , and early death in patients with severe sepsis . background : identification of new therapeutic targets remains an imperative goal to improve the morbidity and mortality associated with severe sepsis and septic shock . macrophage migration inhibitory factor ( MIF ) , a proinflammatory cytokine and counterregulator of glucocorticoids , has recently emerged as a critical mediator of innate immunity and experimental sepsis , and it is an attractive new target for the treatment of sepsis . methods : circulating concentrations of MIF were measured in 2 clinical trial cohorts of 145 pediatric and adult patients who had severe sepsis or septic shock caused predominantly by infection with neisseria meningitidis or other gram negative bacteria , to study the kinetics of MIF during sepsis , to analyze the interplay between MIF and other mediators of sepsis or stress hormones ( adrenocorticotropic hormone and cortisol ) , and to determine whether MIF is associated with patient outcome . results : circulating concentrations of MIF were markedly elevated in 96 of children and adults who had severe sepsis or septic shock , and they remained elevated for several days . MIF levels were correlated with sepsis severity scores , presence of shock , disseminated intravascular coagulation , urine output , blood pH , and lactate and cytokine levels . High levels of MIF were associated with a rapidly fatal outcome . moreover , in meningococcal sepsis , …

Protection from septic shock by neutralization of macrophage migration inhibitory factor. (2000 Feb)
protection from septic shock by neutralization of macrophage migration inhibitory factor . identification of new therapeutic targets for the management of septic shock remains imperative as all investigational therapies , including anti tumor necrosis factor ( TNF ) and anti interleukin ( IL ) 1 agents , have uniformly failed to lower the mortality of critically ill patients with severe sepsis . We report here that macrophage migration inhibitory factor ( MIF ) is a critical mediator of septic shock . High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with bacterial peritonitis . experiments performed in tnfalpha knockout mice allowed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation . Anti MIF antibody protected tnfalpha knockout from lethal peritonitis induced by cecal ligation and puncture ( CLP ) , providing evidence of an intrinsic contribution of MIF to the pathogenesis of sepsis . Anti MIF antibody also protected normal mice from lethal peritonitis induced by both CLP and escherichia coli , even when treatment was started up to 8 hours after CLP . conversely , co injection of recombinant MIF and E . coli markedly increased the lethality of peritonitis . finally , high concentrations of MIF were detected in the plasma of patients with severe sepsis or septic shock . these studies define a critical part for MIF in the pathogenesis of septic shock and identify a new …

Macrophage migration inhibitory factor : gene polymorphisms and susceptibility to inflammatory diseases. (2005 Oct)
macrophage migration inhibitory factor : gene polymorphisms and susceptibility to inflammatory diseases . The cytokine macrophage migration inhibitory factor ( MIF ) is a constitutive element of the host antimicrobial defenses and stress response that promotes proinflammatory function of the innate and acquired immune systems . MIF plays an important role in the pathogenesis of acute and chronic inflammatory or autoimmune disorders , such as sepsis , acute respiratory distress syndrome , asthma , rheumatoid arthritis , and inflammatory bowel diseases . polymorphisms of the human MIF gene ( that is , guanine to cytosine transition at position 173 or CATT tetranucleotide repeat at position 794 ) have been associated with increased susceptibility to or severity of juvenile idiopathic and adult rheumatoid arthritis , ulcerative colitis , atopy , or sarcoidosis . whether these MIF polymorphisms affect the susceptibility to and outcome of sepsis has not yet been examined . analyses of MIF genotypes in patients with sepsis may help to classify patients into risk categories and to identify those patients who may benefit from anti MIF therapeutic strategies .

Increases in serum macrophage migration inhibitory factor in patients with severe sepsis predict early mortality. (2007 Apr)
increases in serum macrophage migration inhibitory factor in patients with severe sepsis predict early mortality . This prospective study aimed to delineate the association between the serum levels of macrophage migration inhibitory factor ( MIF ) and the risks of early mortality in 112 patients who presented with clinically severe sepsis . previous studies showed that elevated serum MIF levels on the first day are associated with an increased risk of 28 day mortality . nonsurvivors may be the sickest population on arrival . Not all patients with severe sepsis follow the same clinical pathway , however , and the sequential change in MIF might be an important predictor of mortality . We hypothesized that , for septic patients , in addition to serum MIF levels on day 1 , the percentage of change in MIF between days 1 and 2 after arriving in the emergency department predicts the probability of early mortality . serum MIF levels were measured on days 1 ( emergency department arrival ) and 2 ( 24 h after arrival ) . patients with a high percentage of increase between MIF levels on days 1 and 2 had higher 3 day ( odds ratio , 1 . 8 ; 95 confidence interval , 1 . 2 2 . 6 ; P 0 . 003 ) and 7 day mortalities ( odds ratio , 1 . 4 ; 95 confidence interval , 1 . 0 1 . 9 ; P 0 . 03 ) after adjusting for …

Macrophage migration inhibitory factor and host innate immune responses to microbes. (2003 Nov)
macrophage migration inhibitory factor and host innate immune responses to microbes . among innate immune cells , macrophages play an essential role in the sensing and elimination of invasive microorganisms . binding of microbial products to pathogen recognition receptors stimulates macrophages to release cytokines and other effector molecules that orchestrate the host innate and adaptive immune responses . recently , the protein known as macrophage migration inhibitory factor ( MIF ) has emerged as a pivotal mediator of innate immunity . first identified as a T cell cytokine , MIF was rediscovered as a protein released by pituitary cells after exposure to endotoxin lipopolysaccharide ( LPS ) or bacteria and in response to stress . monocytes , macrophages and lymphocytes constitutively express MIF , which is rapidly released after stimulation with bacterial endotoxins and exotoxins , and cytokines . MIF induces powerful proinflammatory biological responses and has been shown to be an important effector molecule of septic shock . High levels of MIF have been detected in the circulation of patients with severe sepsis and septic shock . inhibition of MIF activity with neutralizing anti MIF antibodies or deletion of the Mif gene led to a marked reduction in cytokine production and protected mice from lethal bacterial sepsis and toxic shock induced by Gram negative endotoxin or Gram positive exotoxins . investigations into the mechanisms whereby MIF modulates innate immune responses to endotoxin and Gram negative bacteria have shown that MIF up regulates the expression of Toll like receptor 4 …

ISO 1 binding to the tautomerase active site of MIF inhibits its pro inflammatory activity and increases survival in severe … (2005 Oct)
ISO 1 binding to the tautomerase active site of MIF inhibits its pro inflammatory activity and increases survival in severe sepsis . MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis , arthritis , and other inflammatory diseases . antibodies against MIF are effective in experimental models of inflammation , and there is interest in strategies to inhibit its deleterious cytokine activities . Here we identify a mechanism of inhibiting MIF pro inflammatory activities by targeting MIF tautomerase activity . We designed small molecules to inhibit this tautomerase activity ; a lead molecule , ISO 1 ( ( S , R ) 3 ( 4 hydroxyphenyl ) 4 , 5 dihydro 5 isoxazole acetic acid methyl ester ) , significantly inhibits the cytokine activity in vitro . moreover , ISO 1 inhibits tumor necrosis factor release from macrophages isolated from lpstreated wild type mice but has no effect on cytokine release from mifdeficient macrophages . The therapeutic importance of the MIF inhibition by ISO 1 is demonstrated by the significant protection from sepsis , induced by cecal ligation and puncture in a clinically relevant time frame . these results identify ISO 1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis .

Macrophage migration inhibitory factor ( MIF ) modulates innate immune responses induced by endotoxin and Gram negative bacteria. (2001 Dec)
macrophage migration inhibitory factor ( MIF ) modulates innate immune responses induced by endotoxin and Gram negative bacteria . discovered in the early 1960s as a T cell cytokine , MIF has emerged to be an important mediator of the innate immune system . MIF was identified recently to be released by a vast array of cells , including monocytes / macrophages , T cells , B cells , endocrine cells and epithelial cells in response to infection and stress . bacteria , microbial toxins and cytokines have been shown to be powerful inducers of MIF secretion by macrophages . MIF stimulates the expression of pro inflammatory mediators by immune cells and functions to counterbalance the anti inflammatory and immunosuppressive effects of glucocorticoids . Like TNF and IL 1 , MIF plays an important role in host responses to infection . recombinant MIF was found to exacerbate lethal endotoxemia or bacterial sepsis when co injected with LPS or escherichia coli in mice . conversely , MIF knockout mice or mice treated with anti MIF antibodies were protected from shock induced by LPS , staphylococcal exotoxins or bacterial peritonitis , even when anti MIF therapy was started after the onset of infection . given the central role played by MIF in innate immune responses against microbial pathogens and in the regulation of inflammatory responses , pharmacological modulation of MIF production or neutralization of MIF activity could have broad clinical applications and may offer new treatment options for the management of patients …

Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis. (2004 Sep)
macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis . macrophage migration inhibitory factor ( MIF ) is a cytokine playing a critical role in the pathophysiology of experimental sepsis . The purpose of this study was to determine the levels of MIF and to compare those to interleukin 6 ( IL 6 ) levels in predicting mortality among critically ill patients with sepsis . The levels of MIF and IL 6 were measured in 25 patients with septic shock , 17 patients with sepsis , and 11 healthy volunteers . The median plasma concentrations of MIF and IL 6 were significantly higher in patients with septic shock and in patients with sepsis than in healthy controls . MIF levels were significantly different between survivors and nonsurvivors , as were IL 6 levels . discriminatory power in predicting mortality , as assessed by the areas under receiver operating characteristic curves ( auroc ) , was 0 . 793 for MIF and 0 . 680 for IL 6 . finally , high plasma levels of MIF ( 1100 pg / mL ) had a sensitivity of 100 and a specificity of 64 to identify the patients who eventually would evolve to a fatal outcome . Thus , our data suggest that an elevated MIF level in recently diagnosed septic patients appears to be an early indicator of poor outcome and a potential entry criterion for future studies with therapeutic intervention aiming at MIF neutralization .

Insulin in sepsis and septic shock. (2003 Nov)
insulin in sepsis and septic shock . NF kappab activation , and elevated concentrations of macrophage migration inhibitory factor ( MIF ) , tumor necrosis factor alpha ( TNF alpha ) , interleukin 1 ( IL 1 ) , IL 6 , free radicals , inducible nitric oxide ( iNO ) , and stress hyperglycemia occurs in sepsis and this leads to systemic inflammatory response and myocardial depression seen in sepsis and septic shock . conversely , insulin suppresses production of MIF , TNF alpha , IL 1 , IL 6 , and free radicals , enhances endothelial NO generation , and enhances the production of anti inflammatory cytokines IL 4 , and IL 10 , corrects stress hyperglycemia and improves myocardial function . This supports my earlier proposal that insulin ( with or without glucose and potassium ) therapy to maintain euglycemia suppresses the inflammatory response , improves myocardial function , and thus , is of benefit in acute myocardial infarction , sepsis andseptic shock .

Increased susceptibility to septic and endotoxic shock in monocyte chemoattractant protein 1 / cc chemokine ligand 2 deficient mice correlates … (2006 Oct)
increased susceptibility to septic and endotoxic shock in monocyte chemoattractant protein 1 / cc chemokine ligand 2 deficient mice correlates with reduced interleukin 10 and enhanced macrophage migration inhibitory factor production . The chemokine monocyte chemoattractant protein 1 / CC chemokine ligand 2 ( MCP 1 / CCL2 ) is a potent chemoattractant of mononuclear cells and a regulatory mediator involved in a variety of inflammatory diseases . In the present study , we demonstrate that mcp 1 / ccl2 deficient mice are more susceptible to systemic inflammatory response syndrome induced by lipopolysaccharide and to polymicrobial sepsis induced by cecum ligation and puncture ( CLP ) when compared with wild type mice . interestingly , in the CLP model , mcp 1 / ccl2 deficient mice efficiently cleared the bacteria despite an impaired recruitment of leukocytes , especially mononuclear cells . The increased lethality rate in these models correlates with an impaired production of interleukin ( IL ) 10 in vivo . furthermore , macrophages from mcp 1 / ccl2 deficient mice activated with lipopolysaccharide also produced lower amounts of IL 10 and similar tumor necrosis factor compared with wild type mice . We observed a drastic increase in the amounts of macrophage migration inhibitory factor at 6 and 24 h after CLP in mcp 1 / ccl2 deficient mice . these results indicate that endogenous MCP 1 / CCL2 positively regulates IL 10 but negatively controls macrophage migration inhibitory factor during peritoneal sepsis , thus suggesting an important immunomodulatory …