Streptomycin chemical structure
Find information on thousands of medical conditions and prescription drugs.

Streptomycin

Streptomycin was the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus.

It was first isolated on October 19, 1943 by Albert Schatz, a research student at Rutgers University, New Jersey, USA. However, according to academic tradition, Schatz's supervisor, Professor Selman Abraham Waksman, took credit for his student's discovery and received the Nobel prize in Physiology in 1952. Schatz was belatedly awarded the Rutgers medal in 1994, at the age of 74.

Streptomycin cannot be given orally, but must be administered by regular intramuscular injection.

Home
Diseases
Medicines
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
Growth hormone
Salbutamol
Salmeterol
Sandimmune
Sandostatin
Sansert
Saquinavir
Sarafem
Satric
Scopolamine
Seasonale
Secobarbital
Secretin
Selegiline
Semprex-D
Sensipar
Sensorcaine
Serax
Serevent
Serine
Seroquel
Serostim
Serrapeptase
Sertindole
Sertraline
Serzone
Sevelamer
Sevoflurane
Sibutramine
Sildenafil
Silibinin
Simvastatin
Sinemet
Sinequan
Singulair
Sirolimus
Skelaxin
Sodium cyclamate
Solage
Soma
Somatostatin
Sotahexal
Sotalol
Sotret
Spiperone
Spiriva
Spironolactone
Sporahexal
Sporanox
SPS
SSD
Stanozolol
Stavudine
Stelazine
Stilbestrol
Stilbetin
Stimate
Stiripentol
Strattera
Streptokinase
Streptomycin
Suboxone
Subutex
Sucralfate
Sucralfate
Sufentanil
Sulbactam
Sulfamethoxazole
Sulfanilamide
Sulfasalazine
Sulforidazine
Sulla
Sulpiride
Sultamicillin
Sumatriptan
Suprefact
Suramin sodium
Sustaire
Sustiva
Suxamethonium chloride
Symmetrel
Synarel
Synercid
Synthroid
Syntocinon
Zaleplon
T
U
V
W
X
Y
Z

Read more at Wikipedia.org


[List your site here Free!]


Endotoxin Up-regulates Interleukin-18: Potential Role for Gram-Negative Colonization in Sarcoidosis
From American Journal of Respiratory and Critical Care Medicine, 11/15/05 by Kelly, Deirdre M

Rationale and Objectives: Sarcoidosis is a granulomatous disease of unknown etiology characterized by a helper T-cell type 1-mediated process. Previously we demonstrated a role for interleukin-18 in sarcoidosis. Here we examine the regulation of interleukin-18 in this condition.

Methods: Cytokine levels in sarcoid epithelial lining fluid were measured by ELISA. We examined interleukin-18 promoter activity and mRNA and protein levels in the epithelial lining fluid of individuals with active sarcoidosis, and of individuals recovered from sarcoidosis, in response to purified protein derivative of Mycobacterium tuberculosis, beryllium sulfate, zirconium sulfate, aluminum sulfate, and lipopolysaccharide. Endotoxin levels in the epithelial lining fluid of individuals with sarcoidosis, individuals recovered from sarcoidosis, and control subjects were assessed by Limulus amebocyte lysate analysis. Allele-specific polymerase chain reaction was used to genotype 94 patients with sarcoidosis and 97 control subjects for the interleukin-18 -607^sup A/C^ polymorphism. Species-specific polymerase chain reaction identified bacterial DNA in fluid samples.

Results: Epithelial lining fluid from active sarcoids contained elevated levels of interleukin-18, interferon-γ, and interleukin-12 compared with recovered patients and also contained significantly higher levels of endotoxin. Depletion of endotoxin from this epithelial lining fluid reduced its effect on the human interleukin-18 promoter in vitro. There was a higher frequency of the-607^sup C^ allele and -607^sup C/C^ genotype in the sarcoidosis population compared with control subjects; however, this was not associated with a functional response to endotoxin treatment. Finally, bacterial 16S rRNA from Haemophilus influenzae and Moraxella catarrhalis was detected in sarcoid fluid samples.

Conclusions: The pathogenesis of sarcoidosis is propagated through the actions of a helper T-cell type 1-driven response. This study shows that gram-negative bacteria may contribute to this effect by upregulating interleukin-18 expression.

Keywords: cytokines; human; lipopolysaccharide; lung; monocytes/macrophages

Sarcoidosis is a multisystem disease of unknown etiology characterized by a granulomatous inflammatory process (1, 2). It is generally assumed that the pathogenesis of the disease results from genetically susceptible hosts being exposed to particular environmental stimuli. Postulated environmental stimuli include infectious agents and noninfectious environmental factors. The fact that there have been numerous reports of familial clustering of this disease indicates that genetic predisposition plays an important role (3). The presence of noncaseating granulomas is a feature of sarcoidosis and 90% of patients have pulmonary symptoms (4, 5). The primary manifestation of this disease is an accumulation of mononuclear inflammatory cells, mostly activated CD4^sup +^ type 1 helper T lymphocytes (Th1 cells), which produce interleukin (IL)-2 and interferon (IFN)-γ (6-9).

IL-18 plays an important role in the Th1 response by upregulating IFN-γ in synergy with IL-12 (10, 11). IL-18 is primarily a monocyte/macrophage-derived cytokine (12) but is also expressed in dendritic cells, Kupffer cells, keratinocytes, synovial fibroblasts, epithelial cells, and osteoblasts (13). IL-18 and its receptor have been shown to be present at elevated levels in the lungs of patients with sarcoidosis (14-17). It is also an important factor in the regulation of IL-2 expression by pulmonary CD4^sup +^ T lymphocytes through AP-1- and nuclear factor-κB-mediated signaling pathways (17).

Mutations in the regulatory regions of cytokine genes have been associated with susceptibility to an increasing number of complex diseases. One such mutation is found in the IL-18 5'-untranslated region (UTR) promoter (18). The single-nucleotide polymorphism (SNP) -607^sup C/A^ is predicted to be located at a binding site for cAMP-responsive element-binding protein (CREB) (19). At this position a change from cytosine (C) to adenine (A) will disrupt a putative CREB-binding site. Previous studies have shown that this SNP is associated with diabetes, necrotizing enterocolitis, rheumatoid arthritis, the development of postinjury sepsis, and also with sarcoidosis (20-24).

To further understand the role of IL-18 in sarcoidosis we examined the effect of various stimuli and genetic factors on the expression of IL-18. We found that incubation of monocytes with active sarcoid epithelial lining fluid (ELF) increased IL-18 levels significantly, whereas incubation with ELF from patients who had recovered from sarcoidosis (recovered patient ELF) did not. We examined IL-18, IL-12. and IFN-γ levels in active sarcoid ELF, recovered patient ELF, and control subjects and found elevated cytokine concentrations in patients with active sarcoidosis. The most striking data were observed during endotoxin analysis of ELF; it was found that sarcoid ELF contained significantly higher levels than did normal subject or recovered patient ELF. The addition of polymyxin B to sarcoid ELF abrogated IL-18 activity. To further elucidate this we demonstrated the presence of gram-negative bacterial DNA in sarcoid bronchoalveolar lavage (BAL) fluid and further identified Haemophilus influenzae and Moraxella catarrhalis as the gram-negative bacteria present. These observations suggest a potential role for a gram-negative bacteria-driven IL-18 response in sarcoidosis and further characterize the Th1 response in this disorder. Some of the results of these studies have been previously reported in the form of an abstract (25, 26).

METHODS

Study Population

Informed consent for BAL fluid collection, using a protocol approved by the Ethics Committee of Beaumont Hospital (Dublin, Ireland), was obtained from 11 patients with biopsy-proven stage I (54.5%) or stage II (45.5%) sarcoidosis, 6 patients recovered from sarcoidosis, and 11 non-smoking control subjects. Patient and control subject data are presented in Table 1. Patients recovered from sarcoidosis had clinical and radiologic data consistent with quiescence of active disease, having recovered either spontaneously or after treatment with prednisolone. and had a mean duration of disease of 17.6 ± 3.1 mo or less and a minimum of 3 mo without corticosteroid treatment. Patients who had not recovered had a mean duration of active disease of 27.8 ± 4.6 mo or more. BAL was performed as described previously (27). The volume of ELF recovered was quantified by the urea dilution method as described (28). These volumes were 1.11 ± 0.03 ml for the sarcoid group, 1.15 ± 0.03 ml for the recovered group, and 0.766 ± 0.02 ml for the normal group (mean ± SEM). Archived BAL fluid from a further 15 patients with sarcoidosis (17) was used for polymerase chain reaction (PCR) analyses.

A homogeneous Irish population was investigated for the -607^sup A/C^ mutation: 94 patients with sarcoidosis (stage 0, I, II, or III) and 97 healthy control subjects (male:female ratio, 61:33 and 42:55, respectively: mean age ± SEM, 39 ± 3.6 and 75 ± 4.0 yr, respectively).

BAL fluid from nine individuals with chronic obstructive pulmonary disease (four males and five females; FEV^sub 1^, 50 ± 6% predicted) was also evaluated for IL-18 levels.

Cell Culture

Human THP-1 monocytic cells were cultured in Roswell Park Memorial Institute 1640 containing 10% fetal calf serum, 2 mM L-glutamine, penicillin, and streptomycin (Life Technologies, Paisley, UK).

Promoter Analysis

THP-1 cells (1 × 10^sup 6^) were transiently transfected with a human IL-18 5'-UTR-pGL3 (hIL-18 5'-UTR-pGL3) luciferase plasmid (18); cells were left untreated or stimulated with tuberculin-purified protein derivative (PPD, 5 TU; Statens Serum Institut, Copenhagen, Denmark), beryllium sulfate (BeSO^sub 4^, 100 µM), aluminum sulfate (Al^sub 2^[SO^sub 4^]^sub 3^, 25-100 µM), zirconium sulfate (Zr[SO^sub 4^]^sub 3^, 25-100 µM), or LPS (as indicated, Pseudomonas aeruginosa; Sigma-Aldrich, Dublin, Ireland), and/or 10 µl of sarcoid or recovered patient ELF. Twenty-four-hour poststimulation reporter gene expression was determined (29). See the online supplement for additional details.

IL-18 mRNA Analysis

IL-18 transcripts were quantified by reverse transcriptase-PCR (RT-PCT) (29), using primers 5'-TGGCTGCTGAACCAGTAGAA-3' and 5'-ATAGAGGCCGATTTCCTTGG-3' (IL-18) and primers 5'-AAC TCT GGT AAA GTG GAT-3' and 5'-TAC TCA GCG CCA CCA GCA TGC-3' (glyceraldehyde-3-phosphate dehydrogenase). See the online supplement for additional details.

IL-18 Protein Production

IL-18 was measured in supernatants of THP-1 cells (1 × 10^sup 6^/well) by ELISA (R&D Systems, Abingdon, UK). See the online supplement for additional details.

Endotoxin Analysis

LPS activity was measured in BAL fluid samples, using a quantitative chromogenic Limulus amebocyte assay (QCL-1000; Cambrex, Wokingham, UK). See the online supplement for additional details.

Genotyping the -607^sup C/A^ Polymorphism

DNA extracted from peripheral blood leukocytes, using the Wizard Genomic DNA purification kit (Promega, Southampton, UK), was used as a template for allele-specific PCR to genotype the -607^sup A/C^ polymorphism as described previously (18). See the online supplement for additional details.

Bacterial Species-specific PCR

DNA was extracted from BAL fluid by phenol-chloroform extraction and ethanol precipitation. Analysis of DNA for 16S rRNA was described previously (30). Species-specific PCR for H. influenzae (31), M. catarrhalis (32), Pseudomonas spp. (33), Legionella pneumophilia (34), and Chlamydia spp. (35) were described previously (Table 2). See the online supplement for additional details.

Statistical Analysis

Data are expressed as means ± SEM. p values less than 0.05 were considered to be significant (Prism 3.03; GraphPad Software, San Diego, CA). χ^sup 2^ and Fisher exact tests were used to calculate odds ratios and 95% confidence intervals for mutation frequencies in patients with sarcoidosis versus control subjects. Both sarcoidosis and control populations were tested for conformity to exact Hardy-Weinberg equilibrium test for genotype counts at biallelic loci available at the NHLBI Innate Immunity Programs for Genomic Applications (see http://innateimmunity.net/IIPGA2/Bioinformatics/exacthweform).

RESULTS

Cytokine Levels in Sarcoidosis and Recovered Patient ELF

We have previously reported elevated levels of IFN-γ, IL-12, and IL-18 in sarcoid versus recovered patient ELF. To determine whether this is a feature of the granulomatous process or an idiosyncratic feature of the individuals with sarcoidosis, we measured ELF cytokine levels in active and recovered sarcoid patients. IFN-γ, IL-12, and IL-18 levels were all significantly (p

Effect of Sarcoid and Recovered Patient ELF on IL-18 Levels in THP-1 Cells

To determine whether activity of the hIL-18 5'-UTR promoter region was directly activated by sarcoid ELF, THP-1 cells were transiently transfected with a pGL3-5'-UTR-luciferase construct. Compared with unstimulated cells, luciferase activity was threefold higher after stimulation with sarcoid ELF (Figure 2A). When recovered patient ELF was used as the stimulant, no induction of hIL-18 5'-UTR activity was evident. Semiquantitative RT-PCR and ELISA were employed to quantify the effects of sarcoid ELF on IL-18 gene and protein expression in THP-1 cells. Sarcoid ELF significantly increased IL-18 gene expression (Figure 2B). A similar effect was seen on IL-18 protein expression (Figure 2C; 27.4 ± 0.29, 302.7 ± 35.07, and 133.7 ± 27.3 pg of IL-18 per milliliter for control, sarcoid, and recovered ELF, respectively).

Effect of Purified Protein Derivative of Mycobacterium tuberculosis, Beryllium, Aluminum, Zirconium, and LPS on IL-18 Activity

Given that the formation of granulomas also occurs in tuberculosis and chronic beryllium disease, we examined the effect of PPD of M. tuberculosis and BeSO^sub 4^ on IL-18 expression. THP-1 cells were transiently transfected with an hIL-18 5'-UTR-luciferase construct and stimulated with PPD (5 TU), BeSO^sub 4^ (100 µM), or LPS (10 µg) for 24 h. Both BeSO^sub 4^ and LPS significantly upregulated promoter activity (Figure 3A) and also induced IL-18 gene and protein expression in THP-1 cells (Figures 3B and 3C). The BeSO^sub 4^ effect was not inhibited by polymyxin B (data not shown). PPD stimulation did not increase hIL-18 5'-UTR promoter activity (Figure 3A). However, PPD did induce IL-18 mRNA and protein expression in THP-1 cells (Figures 3B and 3C). Dose-response experiments using Al^sub 2^(SO^sub 4^)^sub 3^ (25-100 µM) or Zr(SO^sub 4^)^sub 3^ (25-100 µM) as agonist also increased IL-18 protein production from THP-1 cells (Figures 3D and 3E). with Al^sub 2^(SO^sub 4^)^sub 3^ having a considerably more potent effect than all other agonists.

Determination of Endotoxin Levels in BAL Fluid

Given the potent effect of LPS on IL-18 promoter activity and gene and protein expression, we quantified endotoxin levels in sarcoid, recovered patient, and normal subject BAL fluid. Sarcoid BAL fluid was found to contain a notably higher level of endotoxin (26.0 ± 3.7 EU) compared with recovered patient BAL fluid (7.7 ± 4.3 EU) and healthy control samples (13.5 ± 3.0 EU; Figure 4A). The physiologic level of endotoxin in the sarcoid samples equated to 52 ± 6 ng of LPS per milliliter. The addition of polymyxin B, which binds to and neutralizes LPS, to sarcoid BAL fluid significantly (p

Genetic Analysis of the hIL-18 5'-UTR -607^sup C/A^ Mutation

The hIL-18 5'-UTR -607^sup C/A^ polymorphism disrupts a putative CREB-binding site. A Swedish study revealed that patients with multiple sclerosis and homozygous for cytosine at position -607 had higher levels of IL-18 mRNA compared with patients homozygous for adenine (18). Genotype and allelic frequencies of the -607^sup C/A^ SNP were therefore examined in a homogeneous Irish sample population of 94 patients with sarcoidosis and 97 healthy control subjects. Genotype frequencies were in agreement with Hardy-Weinberg equilibrium. Figure 5A shows the genotypes of three patients: Patient 1 is homozygous for the C allele and Patients 2 and 3 are -607^sup A/C^ heterozygotes. Of the 94 patients with sarcoidosis, 51 were homozygous for the C allele (54.3%), 5 patients were homozygous for the A allele (5.3%), and 38 patients were heterozygotes (40.4%; Figure 5B). The C allele was significantly increased in the sarcoidosis population (p = 0.029; odds ratio, 1.96; 95% confidence interval, 1.258-3.052) compared with the control population. A statistically significant increase was observed for -607^sup C/C^ in the sarcoidosis group (p = 0.0265; χ^sup 2^, df = 7.259, 2). The -607^sup A/A^ genotype was noted as the rare genotype in this sample population as only 5 patients (5.3%) with sarcoidosis and 13 control individuals (13.4%) were homozygous for the A allele.

Effect of the hIL-18 5'-UTR -607^sup C/A^ SNP on Promoter Activity

Our previous experiments examining hIL-18 5'-UTR promoter activity used a plasmid that carried an adenine at position -607. Given that the -607^sup C^ allele was the most predominant in the sarcoidosis group, it was important to determine whether the -607^sup C/A^ SNP leads to a functional effect on IL-18 activity. THP-1 cells were transiently transfected with a pGL3 5'-UTR-luciferase construct that carried either the A or C allele at position -607. After stimulation with physiologic levels of LPS (50 and 100 ng) promoter activity was significantly (p

16S Ribosomal RNA and Bacterial Species-specific PCR

Because of the significantly higher levels of endotoxin present in sarcoid BAL fluid, we sought to determine from what gramnegative bacterial species the endotoxin was derived. To do this we performed 16S rRNA-specific PCR, using primers that amplify a region of the conserved 16S ribosomal RNA gene common to all bacteria. Amplification of a product indicates the presence of bacterial DNA in a sample. We detected the presence of bacterial DNA in 19 of a total of 26 active sarcoidosis BAL fluid samples (73%). To identify the species from which this bacterial DNA was derived, species-specific PCR was employed. DNA from H. influenzae and M. catarrhalis was detected in 69 and 54% of the sarcoid BAL fluid samples, respectively (Figure 6). DNA from Pseudomonas, Chlamydia, or Legionella was not detected. PCR analysis of recovered patient BAL fluid did not detect any bacterial DNA. Analysis of normal BAL fluid detected bacterial DNA in 46.6% of samples; however, this was not derived from any of the species tested above.

DISCUSSION

The current study illustrates that bacterial endotoxin may play an important role in the regulation of IL-18 in sarcoidosis. Sarcoid ELF, but not recovered ELF, induced IL-18 5'-UTR promoter activity and in turn induced IL-18 mRNA and protein production in THP-1 cells. Depletion of LPS by the addition of polymyxin B impaired this effect. Determination of endotoxin levels in sarcoid, recovered patient, and normal BAL fluid samples showed a higher level of LPS present in sarcoid BAL fluid. A subsequent PCR-based method identified the presence of H. influenzae and M. catarrhalis DNA in sarcoidosis BAL fluid. These findings establish a potential role for a gram-negative bacteria-driven IL-18 response in sarcoidosis.

Since sarcoidosis was first described in 1877, much controversy surrounds the elusive causative agent of this disease (36). Exposures to inorganic and organic environmental moieties, such as clay soil, pine tree pollen, and mineral salts, have all been put forward as possible antigens involved in the etiology of sarcoidosis (1). Because the hallmark of this disease is the formation of granulomas, agents that may elicit this response have also been implicated, such as mycobacteria, aluminum, and zirconium (37-39). Interestingly, our studies show that aluminum and zirconium can positively regulate IL-18 protein production from THP-1 cells. The role of infectious agents in sarcoidosis has always been plausible given that some studies have shown an increased frequency of serum antibodies to pathogens such as Propionibacterium acnes and Chlamydia pneumonias (40,41). Propionibacteria have also been isolated from sarcoid lesions and. using quantitative PCR, propionibacterial rRNA was detected in all 15 patients with sarcoidosis in a Japanese study (42, 43). The data presented in this study now implicate H. influenzas and M. catarrhalis in the pathogenesis of sarcoidosis. All the patients with active sarcoidosis had bacterial DNA from either or both of these two species; however, there was no specific pattern. These gram-negative bacteria have been implicated in chronic obstructive pulmonary disease, pneumonia, sinusitis, and chronic bronchitis (44-47). It is possible that patients with sarcoidosis who do not recover, either spontaneously or with treatment, may have impaired bacterial clearance mechanisms, and this could be related to the ability of these individuals to mount an IL-18 response. Although LPS was also detected in normal BAL fluid the levels were significantly lower and derived from different bacterial species than the LPS in the sarcoid samples. Furthermore, the LPS levels in control and recovered sarcoid samples were lower than the lowest effective dose of LPS capable of inducing a physiologic response in the THP-1 cells (50 ng/ml).

IL-18 has the ability to induce IFN-γ production from Th1 cells in synergy with IL-12 (48). We and others have shown that IL-18 is increased in the lungs of patients with sarcoidosis and it has been shown to upregulate IL-2 expression and to activate CD4^sup +^ T lymphocytes (16, 17). IL-18 was shown to be produced by alveolar macrophages and has been found in airway columnar epithelial cells in biopsies from patients with sarcoidosis (16, 49). The IL-18 receptor is a member of the IL-1 receptor/Toll-like receptor (TLR) family and the regulation of the Th1 response has been shown to involve TLRs (50). TLR4 signaling is critical for IL-18 production from macrophages (51) and one study has shown that TLR4-deficient mice showed significantly lower IL-18 levels compared with wild-type mice (52). Studies have also implicated IL-18 in the host response to bacterial infection, with IL-18-deficient mice displaying impaired innate immune responses during pneumococcal pneumonia (53) and Escherichia coli peritonitis (54). In the present study we have detected the presence of gram-negative bacterial DNA in active sarcoid BAL fluid; however, this bacterial DNA is not the factor responsible for inducing IL-18 expression as DNase treatment of sarcoid BAL fluid has no effect on IL-18 inducibility (data not shown). IL-18 levels during the active phase of pulmonary sarcoidosis were also shown to be elevated compared with those of recovered patients.

Sarcoidosis is pathologically similar to chronic beryllium disease-some people have even coined the term "sarcoidosis of known etiology" to describe chronic beryllium disease-yet the disorders develop in response to different antigens, and culminate in the development of noncaseating granulomas. Chronic beryllium disease is characterized by a hypersensitivity to beryllium salts, and previous studies have shown that BeSO^sub 4^ stimulates bronchoalveolar cell release of tumor necrosis factor a, IL-6, and IL-18 (55, 56). In this study, BeSO^sub 4^ was shown to upregulate IL-18 expression from THP-1 cells in vitro. It has been demonstrated elsewhere that IL-18 is induced in response to PPD antigen from M. tuberculosis (57, 58). We have shown that although PPD upregulates IL-18 mRNA and protein expression, it did not act on the 5'-UTR promoter, perhaps suggesting that PPD may induce IL-18 expression by targeting the IL-18 intron-1 promoter. This study indicates that both PPD and BeSO^sub 4^ induce IL-18 mRNA and protein production. Interestingly, M. tuberculosis catalase-peroxidase, but not PPD, has been identified as a tissue antigen associated with sarcoidosis and may be a target of the adaptive immune response driving granulomatous inflammation in sarcoidosis (59). However, BAL fluid from the patients in this study had no previous exposure to beryllium and showed negative cultures and biopsies for tuberculosis infection.

In addition to environmental factors, there is evidence that genetic factors contribute to the pathogenesis of sarcoidosis (1). Much evidence suggests that genetic variability in human leukocyte antigen genes plays a role in sarcoidosis (60). In ACCESS (A Case Control Etiologic Study of Sarcoidosis) the human leukocyte antigen DRB1*1101 allele was associated with sarcoidosis in a population composed of black subjects and white subjects (61). Mutations in genes for angiotensin-converting enzyme, tumor necrosis factor α, C-C chemokine receptor 2, and the vitamin D receptor are also thought to be involved in this disorder (62). The -607^sup C/A^ SNP present in the IL-18 5'-UTR promoter is located at a putative CREB-binding site (18). Patients with multiple sclerosis and homozygous for the -607^sup C/C^ genotype have higher levels of IL-18 compared with patients with other genotypes (18). In this Irish population, the -607^sup C/C^ genotype and the -607^sup C^ allele were found to be the most frequent: however, functional analysis did not reveal any differential activity between the -607^sup A^ and -607^sup C^ allelic variants in response to LPS. In the Japanese sarcoidosis population, the -607^sup A/C^ genotype and the -607^sup A/C^ allele were predominant (24). Taken together, these data suggest that the -607^sup C^ allele may be a genetic risk factor for sarcoidosis and may be in linkage disequilibrium with a functional mutation elsewhere.

In summary, we have demonstrated that gram-negative bacteria may have a role in initiating the inflammatory response in sarcoidosis. This opens up new possibilities for elucidation of the pathogenesis of this condition and therapeutic interventions.

Conflict of Interest Statement: D.M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.M.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.M.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.C.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.J.O. spoke at conferences sponsored by AstraZeneca, Merck Sharp & Dohme, and Boehringer Ingelheim. He also received industry supported grants from AstraZeneca. N.G.M. acted as consultant to Aventis Behring and Baxter Biosciences and served on the Advisory Board for Genaera.

Acknowledgment: The authors thank Dr. Stephen Smith (Department of Clinical Microbiology, Trinity College Dublin) and Dr. Fidelma Filzpatrick (Department of Microbiology, Royal College of Surgeons in Ireland) for their assistance. pGL35'-UTR vectors and Chlamydia pneumoniae DNA were generously provided by Dr. Vilmantas Giedraitis (Karolinska Institute, Sweden) and Prof. Catherine O'Connell (University of Arkansas for Medical Sciences), respectively.

References

1. American Thoracic Society, European Respiratory Society, World Association of Sarcoidosis and Other Granulomatous Disorders. Statement on sarcoidosis. Am J Respir Crit Care Med 1999:160:736-755.

2. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997:336: 1224-1234.

3. Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol 1997:145:234-241.

4. Mitchell DN, Scadding JG, Sarcoidosis. Am Rev Respir Dix 1974;110:774802.

5. Mitchell DN, Scadding JG, Heard BE, Hinson KF. Sarcoidosis: histopathological definition and clinical diagnosis. J Clin Pathol 1977;30:395-398.

6. Agostini C, Facco M, Chilosi M, Semenzato G. Alveolar macrophage-T cell interactions during Th1-type sarcoid inflammation. Microsc Res Tech 2001:53:278-287.

7. Mollers M, Aries SP, Dromann D, Mascher B, Braun J, Dalhoff K. Intracellular cytokine repertoire in different T cell subsets from patients with Sarcoidosis. Thorax 2001:56:487-493.

8. Pinkston P, Bitterman PB, Crystal RG. Spontaneous release of interleukin-2 by lung T lymphocytes in active pulmonary sarcoidosis. N Engl J Med 1983:308:793-800.

9. Saltini C, Spurzem JR, Lee JJ, Pinkston P, Crystal RG. Spontaneous release of interleukin 2 by lung T lymphocytes in active pulmonary sarcoidosis is primarily from the Leu3^sup +^DR^sup +^ T cell subset. J Clin Invest 1986;77:1962-1970.

10. Okamura H, Nagata K, Komatsu T, Tanimoto T, Nukata Y, Tanabe F, Akita K, Torigoe K, Okura T, Fukuda S. A novel costimulatory factor for γ interferon induction found in the livers of mice causes endotoxic shock. Infect Immun 1995:63:3966-3972.

11. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K. Cloning of a new cytokine that induces IFN-γ production by T cells. Nature 1995:378:88-91.

12. Micallef MJ, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M, et al. Interferon-γ-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-γ production. Eur J Immunol 1996:26:1647-1651.

13. McInnes IB, Gracie JA, Leung BP, Wei XQ, Liew FY. Interleukin 18: a pleiotropic participant in chronic inflammation. Immunol Today 2000;21:312-315.

14. Fukami T, Miyazaki E, Matsumoto T, Kumamoto T, Tsuda T. Elevated expression of interleukin-18 in the granulomatous lesions of muscular sarcoidosis. Clin Immunol 2001;101:12-20.

15. Shigehara K, Shijubo N, Ohmichi M, Yamada G, Takahashi R, Okamura H, Kurimoto M, Hiraga Y, Tatsuno T, Abe S, et al. Increased levels of interleukin-18 in patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 2000:162:1979-1982.

16. Shigehara K, Shijubo N, Ohmichi M, Takahashi R, Kon S, Okamura H, Kurimoto M, Hiraga Y, Tatsuno T, Abe S, et al. IL-12 and IL-18 are increased and stimulate IFN-γ production in sareoid lungs. J Immunol 2001;166:642-649.

17. Greene CM, Meachery G, Taggart CC, Rooney CP, Coakley R, O'Neill SJ, McElvaney NG. Role of IL-18 in CD4^sup +^ T lymphocyte activation in sarcoidosis. J Immunol 2000:165:4718-4724.

18. Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol 2001:112:146-152.

19. Haus-Seuffert P, Meisterernst M. Mechanisms of transcriptional activation of cAMP-responsive element-binding protein CREB. Mol Cell Biochem 2000:212:5-9.

20. Kretowski A, Mironczuk K, Karpinska A, Bojaryn U, Kinalski M, Puchalski Z, Kinalska I. Interleukin-18 promoter polymorphisms in type 1 diabetes. Diabetes 2002;51:3347-3349.

21. Heninger E, Treszl A, Kocsis I, Derfalvi B, Tulassay T, Vasarhclyi B. Genetic variants of the interleukin-18 promoter region (-607) influence the course of necrotising enterocolitis in very low birth weight neonates. Eur J Pediatr 2002:161:410-411.

22. Sivalingam SP, Yoon KH, Koh DR, Fong KY. Single-nucleotide polymorphisms of the interleukin-18 gene promoter region in rheumatoid arthritis patients: protective effect of AA genotype. Tissue Antigens 2003:62:498-504.

23. Stassen NA, Breit CM, Norfleel LA, Polk HC Jr. IL-18 promoter polymorphisms correlate with the development of post-injury sepsis. Surgery 2003:134:351-356.

24. Takada T, Suzuki E. Morohashi K, Gejyo F. Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population. Tissue Antigens 2002:60:36-42.

25. Kelly D, Gallagher P, Meachery G, Greene C, Taggart C, O'Neill S, McElvaney NG. Genetic and functional analysis of the 5' UTR IL-18 promoter in sarcoidosis [abstract]. Am J Respir Crit Care Med 2004; 169:A548.

26. Kelly D, Greene C, Gallagher P, Taggart C, Meachery G, O'Neill S, McElvaney NG. Mutation and functional analysis of the human IL-18 promoter in sarcoidosis [abstract]. Eur Cytokine Netw 2003; 14:A93.

27. Klech H, Pohl W. Technical recommendations and guidelines for bronchoalveolar lavage (BAL): report of the European Society of Pneumology Task Group. Eur Respir J 1989:2:561-585.

28. Rennard S, Basset G, Lecossier D, O'Donnell K, Pinkston P, Martin P, Crystal R. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol 1986:60:532538.

29. Walsh DE, Greene CM, Carroll TP, Taggart CC, Gallagher PM, O'Neill SJ, McElvaney NG. Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. 7 Biol Chem 2001:276:35494-35499.

30. Matar GM, Sidani N, Fayad M, Hadi U. Two-step PCR-based assay for identification of bacterial etiology of otitis media with effusion in infected Lebanese children. J Clin Microbiol 1998:36:1185-1188.

31. Ueyama T, Kurono Y, Shirabe K, Takeshila M, Mogi G. High incidence of Haemophilus influenzas in nasopharyngeal secretions and middle ear effusions as detected by PCR. J Clin Microbiol 1995:33:1835-1838.

32. Hendolin PH, Markkanen A, Ylikoski J, Wahlfors JJ. Use of multiplex PCR for simultaneous detection of four bacterial species in middle ear effusions. J Clin Microbiol 1997:35:2854-2858.

33. Purohit HJ, Raje DV, Kapley A. Identification of signature and primers specific to genus Pseudomonas using mismatched patterns of 16S rDNA sequences. BMC Bioinformatics 2003:4:19.

34. Wellinghausen N, Frost C, Marre R. Detection of legionellae in hospital water samples by quantitative real-lime LightCycler PCR. Appl Environ Microbiol 2001:67:3985-3993.

35. Girjes AA, Carrick FN, Lavin MF. Single DNA sequence common to all chlamydial species employed for PCR detection of these organisms. Res Microbiol 1999:150:483-489.

36. Hutchinson J. Case of livid papillary psoriasis. In: Illustrations of clinical surgery. London: J&A Churchill; 1877. p. 42.

37. Mangiapan G, Hance AJ. Mycobactcria and sarcoidosis: an overview and summary of recent molecular biological data. Sarcoidosis 1995:12: 20-37.

38. De Vuyst P, Dumortier L, Schandene M, Estenne M, Verhest A, Yernault JC. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis 1987;135:493-497.

39. Skelton HG, Smith KJ, Johnson FB, Cooper CR, Tyler WF, Lupton GP. Zirconium granuloma resulting from an aluminum zirconium complex: a previously unrecognized agent in the development of hypersensilivity granulomas. J Am Acad Dermatol 1993:28:874-876.

40. Mori Y, Nakata Y, Kataoka M, Ejiri T. Hioka T, Maeda T, Hosoya S, Ohnoshi T, Kimura I. Antibody activity to Propionibacterium acnes in bronchoalveolar lavage fluid in sarcoidosis [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi 1989;27:35-41.

41. Puolakkainen M, Campbell LA, Kuo CC, Leinonen M, Gronhagen-Riska C, Saikku. P. Serological response to Chlamydia pneumoniae in patients with sarcoidosis. J Infect 1996:33:199-205.

42. Homma J, Abe YC, Chosa H, Ueda K, Saegusa J, Nakayama M, Homma H, Washizaki M, Okano H. Bacteriological investigation on biopsy specimens from patients with sarcoidosis. Jpn J Exp Med 1978;48:251255.

43. Ishige I, Usui Y, Takemura T, Eishi Y. Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of Japanese patients with sarcoidosis. Lancet 1999:354:120-123.

44. Sarubbi FA, Myers JW, Williams JJ, Shell CG. Respiratory infections caused by Branhamella catarrhalis: selected epidemiologic features. Am J Med 1990;88:9S-14S.

45. Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review. Clin Microbiol Rev 2001;14: 336-363.

46. Murphy TF. Respiratory infections caused by non-typeable Haemophilus influenzae. Curr Opin Infect Dis 2003;16:129-134.

47. Bandi V, Apicella MA, Mason E, Murphy TF, Siddiqi A, Atmar RL, Greenberg SB. Nontypeable Haemophilus influenzae in the lower respiratory tract of patients with chronic bronchitis. Am J Respir Crit Care Med 2001;164:2114-2119.

48. Dinarello CA. IL-18: a T^sub H^1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol 1999;103:11-24.

49. Cameron LA, Taha RA, Tsicopoulos A, Kurimoto M, Olivenstein R, Wallaert B, Minshall EM, Hamid QA. Airway epithelium expresses interleukin-18. Eur Respir J 1999:14:553-559.

50. Dabbagh K, Lewis DB. Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis 2003:16:199-204.

51. Akira S. Toll-like receptors and innate immunity. Adv Immunol 2001;78: 1-56.

52. Fairweather D, Yusung S, Frisancho S, Barrett M, Gatewood S, Steele R, Rose NR. IL-12 receptor β^sup 1^ and Toll-like receptor 4 increase IL-1β- and IL-18-associated myocarditis and coxsackievirus replication. J Immunol 2003:170:4731-4737.

53. Lauw FN, Branger J, Florquin S, Speelman P, van Dcvenler SJ, Akira S, van der Poll T. IL-18 improves the early antimicrobial host response to pneumococcal pneumonia. J Immunol 2002:168:372-378.

54. Weijer S, Sewnath ME, de Vos AF, Florquin S, van der Sluis K, Gouma DJ, Takeda K, Akira S, van der Poll T. Interleukin-18 facilitates the early antimicrobial host response to Escherichia coli peritonitis. Infect Immun 2003:71:5488-5497.

55. Tinkle SS, Newman LS. Beryllium-stimulated release of tumor necrosis factor-α, interleukin-6. and their soluble receptors in chronic beryllium disease. Am J Respir Crit Care Med 1997:156:1884-1891.

56. Barna BP, Dweik RA, Farver CF, Culver D, Yen-Lieberman B, Thomassen MJ. Nitric oxide attenuates beryllium-induced IFNγ responses in chronic beryllium disease: evidence for mechanisms independent of 1L-18. Clin Immunol 2002:103:169-175.

57. Song CH, Lee JS, Nam HH, Kim JM, Suhr JW, Jung SS, Na MJ, Paik TH, Kim HJ, Park JK, et al. 1L-18 production in human pulmonary and pleural tuberculosis. Scand J Immunol 2002:56:611-618.

58. Lee JS, Song CH, Kim CH, Kong SJ, Shon MJ, Kim HJ, Park JK, Paik TH, Jo EK. Profiles of IFN-γ and its regulatory cytokines (IL-12. IL-18 and IL-K)) in peripheral blood mononuclear cells from patients with multidrug-resistant tuberculosis. Clin Exp Immunol 2002:128: 516-524.

59. Song Z, Marzilli L, Greenlee BM, Chen ES, Silver RF, Askin FB, Teirstein AS, Zhang Y, Cotter RJ, Moller DR. Mycobacterial catalaseperoxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005:201:755-767.

60. Iannuzzi MC. Genetics of sarcoidosis. Monaldi Arch Chest Dis 1998; 53:609-613.

61. Rossman MD, Thompson B, Frederick M, Maliarik M, Iannuzzi MC, Rybicki BA. Pandey JP. Newman LE. Magira E. Beznik-Cizman B, et al. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet 2003:73:720-735.

62. du Bois RM, Goh N, McGrath D, Cullinan P. Is there a role for microorganisms in the pathogenesis of sarcoidosis? J Intern Med 2003:253:4-17.

Deirdre M. Kelly, Catherine M. Greene, Gerard Meachery, Michael O'Mahony, Paula M. Gallagher, Clifford C. Taggart, Shane J. O'Neill, and Noel G. McElvaney

Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland

(Received in original form November 29, 2004; accepted in final form August 10, 2005)

Supported by the Research Committee of the Royal College of Surgeons in Ireland.

Correspondence and requests for reprints should be addressed to Catherine Greene, Ph.D., Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. E-mail: cmgreene@rcsi.ie

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 172. pp 1299-1307, 2005

Originally Published in Press as DOI: 10.1164/rccm.20041-11594OC on August 11, 2005

Internet address: www.atsjournals.org

Copyright American Thoracic Society Nov 15, 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

Return to Streptomycin
Home Contact Resources Exchange Links ebay