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Recurrent airway obstruction (RAO) is a severe chronic respiratory disease affecting horses worldwide, though mostly in the Northern hemisphere.
The gene with the greatest number of indirect interactions with the set of proteins identified is Interleukin 4 Receptor (IL-4R), whose protein has also been detected in BALF.
The pathways generated with IL-4R highlight possible important intracellular signaling cascades implicating, for instance, NFI?B. BackgroundRecurrent airway obstruction (RAO) is a respiratory disease characterized by periods of airway obstruction caused by hyperresponsiveness to inhaled organic molds and endotoxins [1, 2]. ConclusionThe integration of proteomic and genomic data on RAO, collected by two independent approaches, has produced a new set of data that identifies novel interactions which emphasize a central role for IL-4R and SOCS5 and implicate downstream intracellular signaling cascades. MethodsWhole genome scan studyFor the genetic studies, phenotypes were classified using HOARSI (Horse Owner Assessed Respiratory Signs Index), as described in detail elsewhere [37]. Congenital thymic hypoplasia (DiGeorge syndrome) results from the lack of normal development of the third and fourth brachial, or pharyngeal, pouches, which leads to abnormality in the great vessels and to the absence of the thymus and the parathyroids. Clinical manifestations Patients with congenital thymic hy-poplasia have distinctive facial features, including low-set ears, a shortened philtrum, and ocular hypertelorism.
Laboratory tests The T cell defect in children with congenital thymic hypoplasia varies from mild to profound.
As the patient ages, T cell function improves; and usually by the time the child is 5 years of age, skin testing reveals no abnormality in cell-mediated immunity. Thymus transplantation should be undertaken in those infants with congenital thymic hypoplasia who experience frequent infections.
Severe combined immunodeficiency disease (SCID) is characterized by marked depletion of cells that mediate both humoral and cellular immunity—B cells and T cells, respectively.
When any of those receptors, or IL-2R, are engaged by its lig-ands, a cytoplasmic tyrosine kinase (Janus-family tyrosine kinase, or JAK3) bound to the y chain is activated.
ADA deficiency leads to an accumulation of adenosine, adenosine triphosphate (ATP), and deoxy-ATP (dATP). Note: All patients with defects in cell-mediated immunity should receive all tests listed, except the last three, for optimal examination.
CD8 deficiency is a rare form of SCID that results from mutations in the ZAP-70 gene.28,29 ZAP-70 is a tyrosine kinase that binds to the CD3 chain and is involved in signal transduction from the T cell receptor (the TCR-CD3 complex). Another variant of SCID is reticular dysgenesis, a severe combined immunodeficiency with a generalized granulocyte deficiency. Clinical manifestations Chronic pulmonary infections, diarrhea, moniliasis, and failure to thrive are the most common manifestations of SCID.
Hundreds of cases of SCID have been successfully treated by transplantation of bone marrow cells.30 By 3 to 8 months after receiving the bone marrow, these patients show normal delayed hypersensitivity and T cell function and are no longer abnormally susceptible to infection. Immunologic reconstitution with bone marrow cells should be attempted only in specialized centers where comprehensive histocompatibility typing and intensive 24-hour care can be given. The manifestations of GVHD include fever, diarrhea, depression of the bone marrow, splenomegaly, and an erythematous rash on the face, trunk, and extremities. It is possible to establish grafts of half-matched (haploidenti-cal) parental marrow in infants with SCID.
Patients with ADA deficiency have also been treated successfully with infusions of purified adenosine deaminase modified with polyethylene glycol.
Clinical manifestations WAS is characterized by eczema, easy bruising, increased susceptibility to infection (both pyogenic and opportunistic), and bloody diarrhea. WAS patients have been treated with marrow transplantation after receiving irradiation or busulfan and antilymphocyte serum to destroy residual lymphocytes; they have then shown normal immune and platelet functions. Ataxia-telangiectasia (A-T) is a disease associated with defects in cell-mediated immunity and with immunoglobulin deficiencies. Clinical manifestations A-T presents as a progressive neurologic disease that begins in early childhood.
Environmental as well as genetic factors strongly influence the course and prognosis of the disease. Interleukin 21 receptor and chemokine (C-C motif) ligand 24 also showed a large number of interactions with the group of detected proteins. Furthermore, the proposed interaction between SOCS5 and IL-4R could explain how different genes can lead to identical clinical RAO phenotypes, as observed in two Swiss Warmblood half sibling families because these proteins interact upstream of an important cascade where they may act as a functional unit. Clinically, affected horses exhibit a chronic, spontaneous cough, nasal discharge, and increased respiratory efforts associated with an elevation in maximal transpulmonary pressure change compared to healthy horses or horses with inflammatory airway disease (IAD) [3].
Products of the following four gene candidates, SOCS5, IL-7R, PTGER4, and PDE4D, were predicted to directly interact with proteins identified in BALF.
Protein product of IL-27 was found in three indirect interactions, namely HLA-DQB1, C5, and FOXP3 (Table 1). Indeed, these insights formulate the first molecular hypotheses on a proteomic level to explain the observation of genetic heterogeneity in RAO. Congenital thymic hypoplasia is not inherited; rather, it is thought to result from an intrauterine accident occurring before the eighth week of pregnancy. Hypocalcemia from associated parathyroid deficiency is a universal finding and often results in neonatal tetany. Severely affected children do not exhibit delayed hypersensitivity reactions; their lymphocytes do not respond to mitogens or antigens in vitro, nor do they produce lymphokines.
However, the abnormal T cell phenotype—as indicated by a higher than normal ratio of CD4+ to CD8+ T cells—persists for life. Transplantation of fetal thymus results in rapid acquisition of normal T cell function, which is thought to be secondary to production of a thymic hormone secreted by the thymic epithelium. They are designated as T-B- or T-B+, depending on whether B cells are normal or increased (B+) or absent (B-). About half of the cases are caused by a deficiency in the enzyme adenosine deaminase (ADA),25 and another large fraction results from mutations in the recombination-activating genes RAG-1 and RAG-2 2 These recombinase enzymes are required for the gene rearrangements that occur before T cell receptor or immunoglobulin synthesis. It has been shown that dATP poisons ribonucleotide reductase, an enzyme required for DNA synthesis.
The last three tests are for patients suspected of having severe combined immunodeficiency or congenital thymic hypoplasia. CD8+ T cells fail to mature, and mature CD4+ T cells fail to function as a result of the mutations in ZAP-70. Newborns with this disease lack granulocytes in the blood and bone marrow and die of infection within the first few days of life. The lymph nodes are small to absent despite chronic infections, which usually begin at 3 to 6 months of age. If the donor and the recipient are not exceedingly well matched, fatal graft versus host disease (GVHD) will ensue. GVHD can be avoided in those cases if the parental marrow is depleted of T cells before transplantation by passage over lectin columns or by treatment with anti-T cell monoclonal antibody plus complement. The ADA gene has been cloned and inserted into a retroviral vector.31 In a few ADA-deficient children, this vector has been transfected into peripheral blood lymphocytes, which were then reinfused.
Starting in the first months of life, however, there is a decrease in T cells in the paracortical areas of the lymph nodes and a polyclonal expansion of B cells. In WAS patients who do not receive a bone marrow transplant and who experience severe bleeding from thrombocytopenia, splenectomy may be considerably beneficial.
It is characterized by cerebellar ataxia, starting at 18 months of age, followed by increasing tremor and deterioration of mental function. On tests of cell-mediated immunity [see Table 4], some A-T patients are anergic and fail to show delayed hypersensitivity responses to common microbial antigens. Research has been focused on characterization of immunologic factors contributing to inflammatory responses, on genetic linkage analysis, and, more recently, on proteomic analysis of airway secretions from affected horses. Protein products of other genes like that of SOCS5, revealed direct interactions with the IL-4R protein.
This gene is one of the main RAO-candidates in Swiss Warmblood family 2 [20] and is located in a region of ECA15 associated with the disease. This study thus illustrates the value of bioinformatics software for the analysis of large and complex sets of data and offers new approaches for the study of complex immunological diseases such as RAO. Only horses with clinical signs that had persisted for at least 2 months were included in the study. There can be a right-sided aortic arch or tetralogy of Fallot or many other cardiac malformations. In addition to the extent of B cell involvement, the variants also differ in the site of the basic cellular defect, the pathogenetic mechanism, and the mode of inheritance [see Table 3].

Other patients with autosomal recessive T~B- SCID lack the enzyme purine nucleoside phosphorylase (PNP).
Thus, lymphocytes lacking ADA cannot divide until the dATP overload is decreased or removed. This gene therapy procedure has corrected the immunodeficiency in these patients, although it must be repeated periodically.32 Successful gene therapy has also been carried out in X-linked SCID by transducing a Maloney virus vector bearing the gene for the common y chain into bone marrow cells.
An increased incidence of hematopoietic malignancies is seen, starting in the second or third decade of life.
Tests of cell-mediated immunity [see Table 4] show a variety of abnormalities: WAS patients lack isohemagglutinins and are unable to make antibodies to polysac-charides. By 5 years of age, progressive telangiectasia is seen in the vessels of the bul-bar conjunctiva and is later visible on the skin. They may also have abnormal in vitro cell-mediated immune responses and may tolerate allografts. A-T patients usually die of lymphoid malignancies or other causes by the end of their second decade. The goal of this study was to investigate the interactions between eight candidate genes previously identified in a genetic linkage study and proteins expressed in bronchoalveolar lavage fluid (BALF) collected from healthy and RAO-affected horses. The interacting proteins NOD2, RPS6KA5 and FOXP3 found in several pathways are reported regulators of the NFI?B pathway. Endoscopic evaluation of RAO-affected horses reveals excessive mucopurulent exudate in the tracheobronchial tree [4].
ARRB1 and IL-4R are downregulated and FOXP3 is upregulated in RAO horses according to proteomic analysis.
SOCS5 downregulates the cytokine signal transduction by terminating intracellular signaling in a variety of ways. In a similar manner, lymphocytes that lack PNP accumulate guanosine, guanosine triphosphate (GTP), and deoxy-GTP, causing metabolic abnormalities that resemble those seen in ADA deficiency.
Antibody levels are usually low, although occasionally the IgM level is normal; and sometimes, a myeloma component is seen.
Sustained responses have been reported in four of these patients: T cell number and function normalized in these patients, as did B cell function, and infusions of Y globulin were no longer required. The protein encoded by the WAS gene appears to be involved in signal transduction that leads to reorganization of the cytoskeleton when lymphocytes are stimulated, which results in defective collaboration between T cells and B cells. They respond to some protein antigens but not to others; in addition, they may exhibit anergy and may not display positive results to skin tests for the usual bacterial or fungal antigens.
Patients with A-T have a disorder of the cell-cycle checkpoint pathway that results in an extreme hypersensitivity to ionizing radiation. The immune deficiencies in these patients leads to recurrent sinus and bronchial infections and subsequent bronchiectasis.
Cytological analysis of bronchoalveolar lavage fluid (BALF) is characterized by non-septic inflammation with increase in mucus and neutrophils (> 25% of the total nucleated cell count) [2].
This can happen with the ubiquitination and subsequent degradation of the Janus kinase [JAK] and signal transducers and activators of transcription [STAT] receptors. A standardized questionnaire was used to gather information from the horse owners on the animals' history of chronic coughing, increased breathing effort at rest, and nasal discharge. Although patients with congenital thymic hypoplasia produce specific antibodies when they are immunized with various antigens, the antibody response is not quite normal, because secondary responses are lacking. SCID caused by ADA or PNP deficiency can be diagnosed prenatally by amniocentesis because fibroblasts in the amniotic fluid also show the enzymatic defect. Lymphocytes have a markedly abnormal appearance when visualized by scanning electron microscopy. Various pulmonary function tests allow quantification of the degree of airway obstruction [3].The immunological basis for RAO is controversial. SOCS5 is predominantly produced in TH1 cells and inhibits differentiation toward the TH2 cell type. Platelets are abnormally small and few in number.36 Certain mis-sense mutations in the WAS gene lead to a mild disease called X-linked thrombocytopenia. Postmortem examination may disclose abnormalities in the thymus, which is small and deficient in lymphocytes.
A number of studies found that cytokine profiles are consistent with TH2 type response (e.g.
Six proteins (10.7%) show controversial expression from the proteomics results (some peptides up- as well as downregulated in RAO). The classification refers to the period when the horses were exhibiting the most severe clinical signs. Interestingly, the fact that SOCS5 and IL-4R directly interact might give a molecular explanation as to why the disease is clinically indistinguishable in both families [21]. While HOARSI 1 comprises unaffected individuals (severity class 1) RAO in this study is represented in severity class 3, which comprises HOARSI 3 and 4 individuals [37].
Extracellular proteins are involved in lungs' innate immunity (SERPINA1; SFTPD, TF, CFB, C3, C5) and in acquired immunity (IGHG1, IGJ, IGKC), amongst other functions (Table 2). Genetic variations in IL4R and SOCS5 may have various effects during RNA replication or splicing, or may influence protein function and stability. Validation on 33 offsprings of sire 1 and 36 offsprings of sire 2 using comprehensive clinical examination showed that HOARSI 3 and 4 individuals in exacerbation are fully consistent with the RAO phenotype [21].Horses selected for genetic linkage analyses arose from two Warmblood sire half sibling families exhibiting high RAO prevalence. One extracellular protein in particular, lymphotoxin beta (LTB), also operates as a member of the Tumor Necrosis Factor family.
A molecular explanation for disease expression might be that a SOCS5 variant could lead to a protein with a different biological activity that could modulate IL-4R function and lead to the same effect as an IL-4R mutation. The two Warmblood sires showed obvious clinical signs of respiratory distress (nostril flare, increased abdominal lift, or increased respiratory rate) and airway obstruction when stabled in stalls with straw bedding and fed hay, and showed remission of these signs when stabled in a barn complex especially adapted to the requirement of RAO patients (bedding of dust-free shavings; haylage feeding). A study performed with horses affected by summer pasture-associated obstructive pulmonary disease (SPAOPD) revealed that the expression of TH1 and TH2 cytokines varies throughout the year [17].
The majority of cell-membrane proteins participate in immune processes such as adhesive interactions of granulocytes (ITGAM), while others are immunoglobulins (IGHM) or proteins of the Major Histocompatibility Complex class II (HLA-DQB1). As IL-4R and SOCS5 are located upstream in the signaling cascades, genetic mutations of the coding genes might lead to the same phenotype, thus explaining genetic heterogeneity in RAO.PTGER4 and PDE4D are located in a region of ECA21 associated with RAO in both Swiss Warmblood family 1 and 2. A total of 248 horses were included in a whole-genome linkage analysis study using microsatellite markers.
The type and amount of key cytokines and other intracellular regulatory and transcription factors that are expressed upon contact with an antigen modulate the inflammatory response.
They directly interact with an important intracellular molecule that was detected during proteomic analysis, namely ARRB1. These proteins are involved in the induction of NF-I?B (NOD2), protection of cells from oxidative stress (ALDH7A1, GSTT1), or participate in cell lysis and in cell-mediated immune responses (GZMB). These two families and the genetic analyses have been described in detail elsewhere [20, 37]. Segregation and genomic analyses performed on two Swiss Warmblood families have led to the conclusion that the mode of inheritance of RAO is characterized by major gene effects, and that these genes differ between families.
Proteins present in the nucleus, on the other hand, are assumed to play a role in the regulatory mechanisms of apoptosis, cancerogenesis (RBL1, RB1), immune-regulation (FOXP3) and regulation of NF-I?B activity (Table 2).
This anti-apoptotic factor enhances the survival of CD4+ T cells and might be one explanation for autoimmunity in humans suffering from multiple sclerosis [29]. Briefly, a total of 286 microsatellite markers covering the 31 horse autosomes and ECAX were used for this study. In the first of these families, RAO was transmitted in an autosomal recessive mode and the major association was found on equine chromosome 13 (ECA13), whereas in the second, it was transmitted in an autosomal dominant mode and the major association was found on ECA15 [18a€“20]. Finally, IL-7R, a candidate gene from ECA21, directly interacts with FOXP3 which is a regulatory T-cell transcription factor implicated in the pathophysiology of human asthma.IL-4R was examined in this study both as an RAO-gene candidate and as one of the proteins detected by proteomic evaluation of BALF. Fragment amplification using PCR was followed by fragment-length measurement on an ABI 3100 (Applied Biosystems), and genotypes were called using GeneMapper ver.
Interestingly, horses from both families showed no phenotypical differences in the expression of RAO, including clinical scores, endoscopic mucus scores, BALF and tracheo-bronchial secretion cytology, response to methacholine challenge and values of arterial oxygenation [21]. IL-4R was previously identified as an RAO candidate gene on ECA13 in Swiss Warmblood family 1 [19, 20]. These results suggest genetic heterogeneity for the clinical phenotype RAO.Proteomic and peptidomic analyses shed light on the metabolic status of biological systems and represent new approaches in the study of complex diseases like asthma and lung cancer in humans [22] and animal models of human diseases [23]. Recent research in proteomics improved disease phenotype characterization based on peripheral blood biomarkers or BALF cytokines in human suffering from asthma and chronic obstructive pulmonary disease [24, 25].

Since these two genes might be the most promising of all RAO-candidate genes, focusing on the IL-4R-pathway is likely to produce valuable insights into the signaling cascades ultimately leading to the disease. One of the major challenges in proteomic analysis is the large amount of data generated, which makes bioinformatics software capable of processing the information indispensable [22].For the present study, we used genomic and proteomic data previously collected from healthy and RAO-affected horses, and performed a comparison using bioinformatics software (Ingenuity Pathway Analysis [IPAA®]). Horses also had reversible airway obstruction documented by pulmonary function tests following bronchodilator administration or environmental change [2].
The tool "Path Explorer" was used to search for documented molecular interactions based on the IngenuityA® Knowledge Base. A large number of proteins identified by proteomic analysis of BALF (39) interact with the TNF-family in the IL-4R pathway and it is noteworthy that LTB was also identified in BALF. The control horses had no clinical signs attributable to chronic respiratory disease when housed indoors and fed hay and no history of infectious respiratory disease (fever, nasal discharge, and cough) in the past 3 months. These cytokines are mostly membrane-bound, produced by macrophages and T cells, and fulfill multiple functions within immune response mechanisms. All procedures were approved by the Purdue University Animal Care and Use Committee.All horses were maintained on pasture for at least two months with no dry hay supplementation before the beginning of this study. Proteins present in BALF from RAO-affected horses and controls were identified by mass spectrometry [26] and these data were imported into IPAA®. Mast cells can also produce large amounts of TNF-I± [30] and interactions between these cells may be involved in neutrophil recruitment to the airway mucosa.
On Day 1, horses were transported from the pasture to the laboratory and allowed at least 30 minutes to acclimate to the lab environment.
Information about eight candidate genes for RAO identified in a family-based whole-genome scan study [20] was also imported into IPAA® to identify documented pathways linking these candidate genes to the BALF proteins identified with proteomics.
Important functions of TNF-I± that may play a role in the pathophysiology of RAO, are neutrophil recruitment and induction of proinflammatory cytokines via activation of the NFI?B pathway. The evaluation consisted of a complete physical examination and calculation of a clinical score, standard pulmonary function testing (PFT), and BALF cytology.
Thus, this study compares genomic and proteomic data within the framework of IPAA® in order to 1) identify the number of interactions between candidate genes for RAO and proteins detected by proteomic analyses and 2) characterize the interacting proteins and pathways involved. The proteins ITGAM, NOD2, RPS6KA5, and FOXP3 that were detected in the proteomic analysis substantiate the importance of the TNF-family and NFI?B pathways. After the horses recovered from sedation, each pair (one RAO and one control) were stalled in adjacent stalls for the exposure trial.In order to induce signs of acute airway obstruction in the RAO-affected horses, all horses were fed moldy hay and pelleted feed and were bedded on straw. TNF-proteins interact with receptors of the tumor necrosis factor receptor family (TNFR), which in turn communicate with an intracellular signaling pathway known as Tumor Necrosis Factors Receptor Associated Factors (TRAFs). The moldy hay was shaken in the breathing zone of each horse for two minutes twice a day until the clinical score of the RAO-affected horse reached 10 (out of 21 possible; Tesarowski et al. Upregulation of TNF-I± leads to a rapid externalization of granules containing P-selectin (Weibel-Palade bodies), to an increased expression of E-selectin, and to a strong expression of the intercellular adhesion molecule 1 (ICAM-1) in endothelial cells. When the RAO-affected horse had a clinical score of a‰? 10, PFT were performed as previously described [41]. On an intracellular level, TNF-receptor activation leads to apoptosis or to signals that promote new gene expression through activation of NFI?B. Upon completion of the second set of tests, all horses were returned to pasture with no access to dry hay. NOD2 is a cytoplasmic protein that recognizes bacterial proteoglycans and then activates NFI?B. Protein concentration in the BALF supernatant was measured with a BCA Assay (Thermo Scientific Pierce BCA Protein Assay Kit, Thermo Fisher Scientific, Inc., Rockford, IL, USA). For each sample, 100 I?g of protein was incubated with three volumes of cold acetone at -20A°C for 30 minutes to precipitate proteins.
The samples were centrifuged for two minutes to concentrate the protein pellet, and the supernatant was discarded. In humans affected by asthma, FOXP3 protein expression within CD4+CD25high T-cells is significantly decreased compared to controls [31]. Cytokines like IL-8 and TNF-I± are induced by NFI?B activation [32, 33] and may play a role in neutrophil recruitment during an RAO crisis.
This is illustrated by a study that detected high levels of NFI?B activity in bronchial cells of RAO-affected horses in comparison to healthy horses [34]. Therefore, our data highlight several factors that all deserve further investigations in order to evaluate their impact in RAO-pathophysiology, especially regarding the neutrophils recruitment, one of the key mechanisms leading to this disease.The IPAA® platform generates pathways based on experimentally identified genes or proteins reported in the literature. In this study, for each pathway, 277 BALF proteins identified using proteomics and one candidate gene were specified so that IPAA® could indentify interactions. On the final day, 1 I?L of 10% trifluoroacetic acid (TFA) was added to each sample to stop the digestion. This approach presupposes that the likelihood of a candidate gene playing a pivotal role in the pathophysiology of RAO increases if that gene stands in multiple interactions with proteins detected in the proteomic analysis. Each sample was run on a C18 column (C-18 Vydac, 300 A, The Nest Group, Southborough, MA, USA) to remove the majority of the salt from the sample, according to standard laboratory procedure. The "connecting proteins" TNF, IFN-I?, and IL-4 act at the origin of signaling cascades and display pleiotropic effects. Hence their effective concentrations may be low or undetectable, which would explain why they were not detected in the proteomic analysis. Samples were processed in batches, and the peptide pellets were stored at -80A°C until all samples were processed.
Furthermore, the heterogeneity and dynamic nature of RAO suggest that additional proteomic analysis of BALF from a wide range of naturally-occurring cases of RAO is warranted before results from this study may be generalized and the implicated proteins and their effects on the lower airways of horses can be confirmed. Another issue is that IPAA® builds connections based on literature from humans, mice, rats and cell cultures.
Although fundamental immune and inflammatory pathways are conserved, there may be some important interspecies differences. Furthermore, transcriptomic and metabolomic analyses might provide much-needed information about smaller molecules (e.g.
LC-MS chromatograms were acquired in positive ion mode under the following conditions: a capillary voltage of 1850 V and an end plate offset of 500 V. For instance, microarray assays and differential display polymerase chain reaction (DD PCR) have already been used to explore differential gene expression in RAO [35, 36]. Ultimately, integration of information gained from all of these approaches may be needed to better understand the complex molecular pathogenesis of RAO.
Briefly, spectral deconvolution was performed to filter noise in the spectra and to separate overlapping peptide peaks.
Peak alignment was used to adjust for retention time drift between samples over the time course of the LC-MS data acquisition. After the pre-processing was complete, the mean intensity of each peak was calculated for each group (RAO-affected and control) and the fold change of each peptide between groups was calculated.
Only peptides with a score of 5 or higher were considered true positives.Peak identificationPeak identification was performed for one RAO-affected horse and one control horse.
The output files from the PDP statistical analysis and Spectrum Mill peptide identification were merged into one file. The reason was that we first intended to explore their global interaction with the candidate genes (i.e. Search results were restricted to molecular interactions described in lung tissues, immune cells, BALF and sputum, genetic disorders, hypersensitivity, immunological diseases, infectious diseases, and inflammatory diseases in humans, mice, rats and cell cultures. Possible types of interaction were "binds to", "inhibits", "acts on", "leads to" and "translocates to". Direct interactions were defined as two molecules making direct physical contact with each other with no intermediate step.
Direct interactions also included chemical modifications such as phosphorylations, provided that there was evidence that the two factors involved interact directly rather than through an intermediate. Indirect interactions are genetic or molecular relationships explicitly reported in the literature and not inferred.
For instance, up-regulation of TNF-I± leads to a strong expression of the intercellular adhesion molecule 1 (ICAM-1) in endothelial cells without direct physical contact between TNF-I± and ICAM-1.

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