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Richard S Hotchkiss

Publications and source records attributed to Richard S Hotchkiss.

At least 19 recordsLinked to original sources
PubMed2007

TAT-Bim induces extensive apoptosis in cancer cells.

BACKGROUND: Suppression of apoptosis is central to the development of cancer and is associated with resistance to modern adjuvant treatments. Therefore, molecules and pathways of apoptotic processes are critical targets for the development of anti-cancer therapeutics. Since apoptosis is executed by intracellular proteins, molecular approaches must incorporate a method to deliver the treatment into the tumor cells. METHODS: We utilized a peptide that contains two domains, a peptide transduction domain derived from the HIV-1 TAT protein and a biological effector domain, the BH3 domain from the pro-apoptotic Bcl-2 family member Bim. We examined whether this construct (TAT-Bim) induced apoptosis in several cancer cell lines (T-cell lymphoma (EL4), pancreatic cancer (Panc-02), and melanoma (B16)) and whether TAT-Bim treatment synergized with radiation. A mutant TAT-Bim peptide with no biologic activity (TAT-Bim-inactive) was used as a control. C57/BL6 mice were challenged with syngeneic cancer cell lines and the effects of intratumoral TAT-Bim injection on tumor growth and host survival were determined. RESULTS: TAT-Bim was internalized by all cancer cells within two hours. TAT-Bim resulted in apoptosis in a dose dependent fashion in all cell lines and sublethal irradiation augmented the effects of TAT-Bim induced apoptosis. TAT-Bim significantly slowed tumor growth in murine models of pancreatic cancer and melanoma. CONCLUSION: TAT-Bim exemplifies a strategy for cancer therapy that involves inducing apoptosis by antagonizing the endogenous anti-apoptotic machinery. Small peptide therapeutics, in combination with traditional adjuvant therapies such as radiation, may provide a valuable 'second hit' and drive tumor cells into programmed cell death.

Animals↗
PubMed2006

Adoptive transfer of dying cells causes bystander-induced apoptosis.

The anti-apoptotic Bcl-2 protein has the remarkable ability to prevent cell death from several noxious stimuli. Intriguingly, Bcl-2 overexpression in one cell type has been reported to protect against cell death in neighboring non-Bcl-2 overexpressing cell types. The mechanism of this "trans" protection has been speculated to be secondary to the release of a cytoprotective factor by Bcl-2 overexpressing cells. We employed a series of adoptive transfer experiments in which lymphocytes that overexpress Bcl-2 were administered to either wild type mice or mice lacking mature T and B cells (Rag-1-/-) to detect the presence or absence of the putative protective factor. We were unable to demonstrate "trans" protection. However, adoptive transfer of apoptotic or necrotic cells exacerbated the degree of apoptotic death in neighboring non-Bcl-2 overexpressing cells (p < or= 0.05). Therefore, this data suggests that dying cells emit signals triggering cell death in neighboring non-Bcl-2 overexpressing cells, i.e., a "trans" destructive effect.

Adoptive Transfer↗
PubMed2006

The role of TCR engagement and activation-induced cell death in sepsis-induced T cell apoptosis.

Sepsis induces extensive apoptosis in T and B cells suggesting that the loss of immune effector cells could be one explanation for the profound immunosuppression observed in this disorder. Unfortunately, the mechanisms responsible for lymphocyte apoptosis in sepsis remain unknown. In T cells, apoptosis can occur through activation-induced cell death (AICD) in which engagement of the Ag receptors by cognate Ag or polyclonal activators such as bacteria-derived superantigens induces activation, proliferation, and apoptosis. We examined whether proliferation and AICD are necessary for apoptotic cell death in sepsis using normal and TCR transgenic mice. Results show that although sepsis resulted in activation of a small percentage of T cells, no proliferation was detected during the first 48 h following onset, a time when extensive apoptosis is observed. We also observed that T cells do not enter the cell cycle, and stimulation via the TCR in TCR transgenic animals does not enhance or decrease cell death in sepsis. Interestingly, T cells recovered from septic mice retained their ability to proliferate and synthesize cytokines albeit at reduced levels. With the exception of IL-10, which was increased in lymphocytes from mice with sepsis, sepsis caused a decrease in the production of both proinflammatory and anti-inflammatory cytokines. We conclude that lymphocyte apoptosis in sepsis does not require proliferation, TCR engagement, or AICD. Thus the immunosuppression observed in sepsis cannot be the result of T cell deletion via the TCR.

Animals↗
PubMed2006

Apoptosis and caspases regulate death and inflammation in sepsis.

Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells. Rectification of this apoptotic-inflammatory imbalance using modulators of caspases and other components of the cell-death pathway have shown striking efficacy in stringent animal models of sepsis, indicating an entirely novel path forward for the clinical treatment of human sepsis.

Animals↗
PubMed2006

Molecular diagnostics in sepsis: from bedside to bench.

BACKGROUND: Based on recent in vitro data, we tested the hypothesis that microarray expression profiles can be used to diagnose sepsis, distinguishing in vivo between sterile and infectious causes of systemic inflammation. STUDY DESIGN: Exploratory studies were conducted using spleens from septic patients and from mice with abdominal sepsis. Seven patients with sepsis after injury were identified retrospectively and compared with six injured patients. C57BL/6 male mice were subjected to cecal ligation and puncture, or to IP lipopolysaccharide. Control mice had sham laparotomy or injection of IP saline, respectively. A sepsis classification model was created and tested on blood samples from septic mice. RESULTS: Accuracy of sepsis prediction was obtained using cross-validation of gene expression data from 12 human spleen samples and from 16 mouse spleen samples. For blood studies, classifiers were constructed using data from a training data set of 26 microarrays. The error rate of the classifiers was estimated on seven de-identified microarrays, and then on a subsequent cross-validation for all 33 blood microarrays. Estimates of classification accuracy of sepsis in human spleen were 67.1%; in mouse spleen, 96%; and in mouse blood, 94.4% (all estimates were based on nested cross-validation). Lists of genes with substantial changes in expression between study and control groups were used to identify nine mouse common inflammatory response genes, six of which were mapped into a single pathway using contemporary pathway analysis tools. CONCLUSIONS: Sepsis induces changes in mouse leukocyte gene expression that can be used to diagnose sepsis apart from systemic inflammation.

Adolescent↗
PubMed2006

Agonistic monoclonal antibody against CD40 receptor decreases lymphocyte apoptosis and improves survival in sepsis.

Sepsis causes a marked apoptosis-induced depletion of lymphocytes. The degree of lymphocyte apoptosis during sepsis strongly correlates with survival. CD40, a member of the TNFR family, is expressed on APCs and has potent antiapoptotic activity. In this study we determined whether an agonistic Ab against CD40 could protect lymphocytes from sepsis-induced apoptosis. Secondly, we examined potential antiapoptotic mechanisms of the putative protection. Lastly, we aimed to determine whether anti-CD40 treatment could improve survival in sepsis. CD1 mice were made septic by the cecal ligation and puncture method and treated postoperatively with anti-CD40 Ab. Treatment with anti-CD40 completely abrogated sepsis-induced splenic B cell death and, surprisingly, decreased splenic and thymic T cell death as well (p < 0.001). To investigate the mechanism of protection of anti-CD40 therapy on T cells, CD40 receptor expression was examined. As anticipated, the CD40 receptor was constitutively expressed on B cells, but, unexpectedly, splenic and thymic T cells were found to express CD40 receptor during sepsis. Furthermore, CD4+CD8- T cells were the predominant subtype of T cells expressing CD40 receptor during sepsis. Additionally, the antiapoptotic protein Bcl-x(L) was found to be markedly increased in splenic B and T cells as well as in thymic T cells after treatment with anti-CD40 Ab (p < 0.0025). Lastly, mice that were made septic in a double injury model of sepsis had improved survival after treatment with anti-CD40 as compared with controls (p = 0.05). In conclusion, anti-CD40 treatment increases Bcl-x(L), provides nearly complete protection against sepsis-induced lymphocyte apoptosis, and improves survival in sepsis.

Animals↗
PubMed2006

TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo.

Apoptosis is a key pathogenic mechanism in sepsis that induces extensive death of lymphocytes and dendritic cells, thereby contributing to the immunosuppression that characterizes the septic disorder. Numerous animal studies indicate that prevention of apoptosis in sepsis improves survival and may represent a potential therapy for this highly lethal disorder. Recently, novel cell-penetrating peptide constructs such as HIV-1 TAT basic domain and related peptides have been developed to deliver bioactive cargoes and peptides into cells. In the present study, we investigated the effects of sepsis-induced apoptosis in Bcl-x(L) transgenic mice and in wild-type mice treated with an antiapoptotic TAT-Bcl-x(L) fusion protein and TAT-BH4 peptide. Lymphocytes from Bcl-x(L) transgenic mice were resistant to sepsis-induced apoptosis, and these mice had a approximately 3-fold improvement in survival. TAT-Bcl-x(L) and TAT-BH4 prevented Escherichia coli-induced human lymphocyte apoptosis ex vivo and markedly decreased lymphocyte apoptosis in an in vivo mouse model of sepsis. In conclusion, TAT-conjugated antiapoptotic Bcl-2-like peptides may offer a novel therapy to prevent apoptosis in sepsis and improve survival.

Animals↗
PubMed2006

Splenic CD4+ T cells have a distinct transcriptional response six hours after the onset of sepsis.

BACKGROUND: In animal and human autopsy studies of sepsis, CD4+ splenocytes either undergo apoptosis or are polarized to the Th2 effector subtype. In mice, these changes occur within 24 hours of the onset of sepsis. Preventing the loss of CD4+ T cells and the Th2-polarization of CD4+ T cells provides a significant survival advantage in mouse models of sepsis. The molecular mechanism(s) for the phenotypic changes of splenic CD4+ T cells in sepsis are not well understood. STUDY DESIGN: CD4+ splenocytes were enriched by negative selection from disaggregated spleens of septic and sham-operated mice at 6 and 24 hours after surgery. Phenotypic analysis using cell surface markers (CD25, CD44, CD62L, CD69), cytokine secretion in response to CD3/CD28 coligation, and whole genome microarray gene expression profiles were obtained for these cells. RESULTS: Consistent with previous reports, sepsis induced a progressive decrease in the number of CD4+ splenocytes and a time-dependent alteration in CD4+ T-cell phenotype. At 6 hours, when no differences in cell number or surface marker expression were observed, significant alterations in RNA abundance were measured for 498 probe sets. Ontologic classification of these genes indicated changes in cellular physiology. Pathway analysis indicated that T-cell receptor signaling and mitogen-activated protein kinase signaling were significantly altered by sepsis. CONCLUSIONS: These data demonstrated a sepsis-specific transcriptional program that precedes sepsis-induced phenotypic changes in CD4+ splenocytes.

Animals↗
PubMed2006

Pneumonia after cecal ligation and puncture: a clinically relevant "two-hit" model of sepsis.

Sepsis continues to be the primary cause of death among patients in surgical intensive care units. In many cases, death does not result from the initial septic event but rather from subsequent nosocomial infection with pneumonia being the most common etiology. In addition, most deaths in patients with sepsis occur after the first 72 h. By contrast, in most animal models of sepsis, most deaths occur within the first 72 h. The purpose of this study was to develop a clinically relevant "two-hit" model of sepsis that would reflect delayed mortality because of secondary nosocomial infection. The well-accepted and widely used cecal ligation and puncture (CLP) model was used as the "first hit". Pseudomonas aeruginosa or Streptococcus pneumoniae was used to induce pneumonia in mice 72 h after CLP as a "second hit." In this study, mortality in mice undergoing CLP followed by pneumonia was significantly higher than in mice receiving pneumonia or CLP alone. S. pneumoniae pneumonia after CLP resulted in a 95% mortality compared with a 20% mortality for pneumonia alone, P < 0.0001. Similarly, mortality of P. aeruginosa pneumonia after CLP (85%) was significantly higher than P. aeruginosa alone (20%), P < 0.0001. Mice undergoing CLP followed by P. aeruginosa pneumonia also had significantly higher levels of B- and T-cell apoptotic death. Finally, mice undergoing CLP followed by P. aeruginosa or S. pneumoniae pneumonia had significantly decreased concentrations of proinflammatory mediators monocyte chemoattractant protein-1 and interleukin (IL)-6 compared with mice undergoing CLP or pneumonia alone. In conclusion, a primary sublethal infection impairs the immune system thus rendering the host more susceptible to secondary infection and death. Double injury, that is, CLP followed by pneumonia, provides a useful tool in the study of sepsis, creating a prolonged period of infection as opposed to CLP alone. The extended duration of infection may lead to a better understanding of the mechanism of the immune dysregulation seen in clinical sepsis and therefore provides for evaluation of potential therapies that target specific stages of the immune response.

Animals↗
PubMed2006

Both gram-negative and gram-positive experimental pneumonia induce profound lymphocyte but not respiratory epithelial cell apoptosis.

To determine whether and by which pathway (via the death receptor or mitochondrial mediated pathway) lymphocyte apoptosis occurs in pneumonia and to determine if increased bronchial epithelial cell apoptosis occurs in pneumonia. Prospective randomized study in a university research laboratory. Male C57BL/6 mice (n = 30). Animals received an intratracheal injection of Streptococcus pneumoniae or Pseudomonas aeruginosa to induce gram-positive or gram-negative pneumonia, respectively and were killed 24, 30, or 48 h later. Presence of pneumonia was confirmed via gross visual examination of lungs and by histology. Lymphocyte apoptosis in spleen and thymus was analyzed by flow cytometry for active caspases 3, 8, and 9 and by immunohistochemical (IHC) staining for active caspase 3 and DNA strand breaks. Respiratory epithelial cell apoptosis was assessed by IHC. Histologically, pneumonia was present in all bacteria-treated animals but none in sham-treated mice. Extensive lymphocyte apoptosis in spleen and thymus was documented by characteristic morphological changes on hematoxylin and eosin staining and by IHC staining in both S. pneumonia and P. aeruginosa infection. Flow cytometry confirmed IHC and showed apoptotic lymphocytes positive for active caspases 3, 8, and 9 in both thymi and spleens in both infections. In contrast to the extensive lymphocyte apoptosis, only rare scattered apoptotic changes were seen in respiratory epithelial or endothelial cells in pneumonia due to either organism. Increased lymphocyte but not bronchial cell apoptosis occurs in both gram-positive and gram-negative pneumonia and probably involves both the extrinsic and intrinsic pathway.

Animals↗
PubMed2005

Prevention of lymphocyte apoptosis--a potential treatment of sepsis?

Sepsis is the leading cause of death in surgical intensive care units and is a major cause of morbidity and mortality in neonatal and medical intensive care units. The Centers for Disease Control and Prevention estimates that, in the United States alone, approximately 500,000 people develop sepsis and 175,000 people die each year. Sepsis is a growing problem; its incidence has tripled from 1972 to 1992. Recently, apoptosis has been identified as an important mechanism of cell death in animal models of sepsis and endotoxemia. During sepsis, there is extensive apoptotic death of lymphocytes and gastrointestinal epithelial cells. The extensive apoptotic death of lymphocytes is likely an important cause of the profound immunosuppression that is a hallmark of patients with sepsis. The apoptosis of gastrointestinal epithelial cells may compromise the integrity of the bowel wall, resulting in translocation of bacteria or endotoxins into the systemic circulation. The potential importance of apoptosis in the pathophysiology of sepsis is illustrated by results from animal models that demonstrate that blocking lymphocyte apoptosis improves survival in sepsis. A variety of strategies to inhibit apoptosis may ultimately provide an effective therapy for this highly lethal disorder.

Animals↗
PubMed2005

Early antibiotic administration but not antibody therapy directed against IL-6 improves survival in septic mice predicted to die on basis of high IL-6 levels.

Elevated interleukin (IL)-6 levels correlate with increased mortality following sepsis. IL-6 levels >14,000 pg/ml drawn 6 h after cecal ligation and puncture (CLP) are associated with 100% mortality in ND4 mice, even if antibiotic therapy is initiated 12 h after septic insult. Our first aim was to see whether earlier institution of antibiotic therapy could improve overall survival in septic mice and rescue the subset of animals predicted to die on the basis of high IL-6 levels. Mice (n = 184) were subjected to CLP, had IL-6 levels drawn 6 h later, and then were randomized to receive imipenem, a broad spectrum antimicrobial agent, beginning 6 or 12 h postoperatively. Overall 1-wk survival improved from 25.5 to 35.9% with earlier administration of antibiotics (P < 0.05). In mice with IL-6 levels >14,000 pg/ml, 25% survived if imipenem was started at 6 h, whereas none survived if antibiotics were started later (P < 0.05). On the basis of these results, we examined whether targeted antibody therapy could improve survival in mice with elevated IL-6 levels. A different cohort of mice (n = 54) had blood drawn 6 h after CLP, and then they were randomized to receive either monoclonal anti-IL-6 IgG or irrelevant rat IgG. Anti-IL-6 antibody failed to improve either overall survival or outcome in mice with IL-6 levels >14,000 pg/ml. These results demonstrate that earlier systemic therapy can improve outcome in a subset of mice predicted to die in sepsis, but we are unable to demonstrate any benefit in similar animals using targeted therapy directed at IL-6.

Animals↗
PubMed2005

Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways.

Patients with sepsis are immune compromised, as evidenced by their failure to clear their primary infection and their propensity to develop secondary infections with pathogens that are often not particularly virulent in normal healthy individuals. A potential mechanism for immunosuppression in sepsis is lymphocyte apoptosis, which may occur by either a death receptor or a mitochondrial-mediated pathway. A prospective study of blood samples from 71 patients with sepsis, 55 nonseptic patients, and 6 healthy volunteers was undertaken to quantitate lymphocyte apoptosis and determine cell death pathways and mechanisms of apoptosis. Apoptosis was evaluated by flow cytometry and Western blotting. Lymphocyte apoptosis was increased in CD4 and CD8 T cells, B cells (CD20), and NK cells (CD56) in septic vs nonseptic patients. Samples taken sequentially from 10 patients with sepsis showed that the degree of CD3 T cell apoptosis correlated with the activity of his/her sepsis. In septic patients, apoptotic lymphocytes were positive for active caspases 8 and 9, consistent with death occurring by both mitochondrial-mediated and receptor-mediated pathways. In support of the concept that both death pathways were operative, lymphocyte apoptosis occurred in cells with markedly decreased Bcl-2 (an inhibitor of mitochondrial-mediated apoptosis) as well as cells with normal concentrations of Bcl-2. In conclusion, apoptosis occurs in a broad range of lymphocyte subsets in patients with sepsis and correlates with the activity of the disease. Lymphocyte loss occurs by both death receptor and mitochondrial-mediated apoptosis, suggesting that there may be multiple triggers for lymphocyte apoptosis.

Adult↗
PubMed2005

Iron dysregulation combined with aging prevents sepsis-induced apoptosis.

BACKGROUND: Sepsis, iron loading, and aging cause independent increases in gut epithelial and splenic apoptosis. It is unknown how their combination will affect apoptosis and systemic cytokine levels. MATERIALS AND METHODS: Hfe-/- mice (a murine homologue of hemochromatosis) abnormally accumulate iron in their tissues. Aged (24-26 months) or mature (16-18 months) Hfe-/- mice and wild type (WT) littermates were subjected to cecal ligation and puncture (CLP) or sham laparotomy. Intestine, spleen, and blood were harvested 24 h later and assessed for apoptosis and cytokine levels. RESULTS: Gut epithelial and splenic apoptosis were low in both aged septic and sham Hfe-/- mice, regardless of the amount of iron in their diet. Mature septic WT mice had increased apoptosis compared to age-matched sham WT mice. Mature septic Hfe-/- mice had similar levels of intestinal cell death to age-matched septic WT mice but higher levels of splenic apoptosis. Apoptosis was significantly lower in septic aged Hfe-/- mice than septic mature Hfe-/- animals. Interleukin-6 was elevated in septic aged Hfe-/- mice compared to sham mice. CONCLUSIONS: Although sepsis, chronic iron dysregulation, and aging each increase gut and splenic apoptosis, their combination yields cell death levels similar to sham animals despite the fact that aged Hfe-/- mice are able to mount an inflammatory response following CLP and mature Hfe-/- mice have elevated sepsis-induced apoptosis. Combining sepsis with two risk factors that ordinarily increase cell death and increase mortality in CLP yields an apoptotic response that could not have been predicted based upon each element in isolation.

Aging↗
PubMed2005

Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury.

OBJECTIVES: The aim of this study was to determine the effects of acute lung injury on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined. DESIGN: Randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Genetically inbred mice. INTERVENTIONS: Following induction of acute lung injury, gut epithelial proliferation and apoptosis were assessed in a) C3H/HeN wild-type and C3H/HeJ mice, which lack functional Toll-like receptor 4 (n = 17); b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-alpha or control antibody (n = 22); and c) C57Bl/6 wild-type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n = 21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n = 24) as well as in a time course analysis following a fixed injury (n = 18). MEASUREMENTS AND MAIN RESULTS: Acute lung injury caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-tumor necrosis factor-alpha antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe acute lung injury. Changes in both gut epithelial proliferation and death were apparent within 12 hrs, but proliferation was decreased 36 hrs following acute lung injury while apoptosis returned to normal. CONCLUSIONS: Acute lung injury causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving Toll-like receptor 4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the gut epithelium, and acute lung injury-induced changes in intestinal epithelial proliferation persist longer than those in apoptosis.

Animals↗
PubMed2004

Akt decreases lymphocyte apoptosis and improves survival in sepsis.

Sepsis induces extensive death of lymphocytes that may contribute to the immunosuppression and mortality of the disorder. The serine/threonine kinase Akt is a key regulator of cell proliferation and death. The purpose of this study was to determine whether overexpression of Akt would prevent lymphocyte apoptosis and improve survival in sepsis. In addition, given the important role of Akt in cell signaling, T cell Th1 and Th2 cytokine production was determined. Mice that overexpress a constitutively active Akt in lymphocytes were made septic, and survival was recorded. Lymphocyte apoptosis and cytokine production were determined at 24 h after surgery. Mice with overexpression of Akt had a marked improvement in survival compared with wild-type littermates, i.e., 94 and 47% survival, respectively, p < 0.01. In wild-type littermates, sepsis caused a marked decrease in IFN-gamma production, while increasing IL-4 production >2-fold. In contrast, T cells from Akt transgenic mice had an elevated production of IFN-gamma at baseline that was maintained during sepsis, while IL-4 had little change. Akt overexpression also decreased sepsis-induced lymphocyte apoptosis via a non-Bcl-2 mechanism. In conclusion, Akt overexpression in lymphocytes prevents sepsis-induced apoptosis, causes a Th1 cytokine propensity, and improves survival. Findings from this study strengthen the concept that a major defect in sepsis is impairment of the adaptive immune system, and suggest that strategies to prevent lymphocyte apoptosis represent a potential important new therapy.

Animals↗
PubMed2004

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.

Africa↗