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G K Haines

Publications and source records attributed to G K Haines.

At least 37 records · Page 2Linked to original sources
PubMed1999

The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis.

The chemokine, epithelial neutrophil-activating peptide-78 (ENA-78), is a potent neutrophil chemotaxin whose expression is increased in inflamed synovial tissue and fluid in human rheumatoid arthritis compared with osteoarthritis. Since ENA-78 has been implicated in the pathogenesis of RA, we examined the expression of an ENA-78-like protein during the development of rat adjuvant-induced arthritis (AIA). Using an ELISA assay, we found increased levels of antigenic ENA-78-like protein in the sera of AIA animals compared with control normal animals by day 7 postadjuvant injection. ENA-78-like protein levels continued to increase as AIA developed. ENA-78-like protein levels in joint homogenates were increased in AIA animals later in the development of the disease, by day 18 during maximal arthritis, compared with control animals. Expression of ENA-78-like protein in both the AIA serum and joint correlated with the progression of inflammation of the joints. Anti-human ENA-78 administered before disease onset modified the severity of AIA, while administration of anti-ENA-78 after clinical onset of AIA did not modify the disease. These data support a role for an ENA-78-like protein as an important chemokine in the progression and maintenance of AIA.

Animals↗
PubMed1999

pp60(v-src) induction of cyclin D1 requires collaborative interactions between the extracellular signal-regulated kinase, p38, and Jun kinase pathways. A role for cAMP response element-binding protein and activating transcription factor-2 in pp60(v-src) signaling in breast cancer cells.

The cyclin D1 gene is overexpressed in breast tumors and encodes a regulatory subunit of cyclin-dependent kinases that phosphorylate the retinoblastoma protein. pp60(c-src) activity is frequently increased in breast tumors; however, the mechanisms governing pp60(c-src) regulation of the cell cycle in breast epithelium are poorly understood. In these studies, pp60(v-src) induced cyclin D1 protein levels and promoter activity (48-fold) in MCF7 cells. Cyclin D1-associated kinase activity and protein levels were increased in mammary tumors from murine mammary tumor virus-pp60(c-src527F) transgenic mice. Optimal induction of cyclin D1 by pp60(v-src) involved the extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase members of the mitogen-activated protein kinase family. Cyclin D1 promoter activation by pp60(v-src) involved a cAMP response element-binding protein (CREB)/activating transcription factor 2 (ATF-2) binding site. Dominant negative mutants of CREB and ATF-2 but not c-Jun inhibited pp60(v-src) induction of cyclin D1. pp60(v-src) induction of CREB was blocked by the p38 inhibitor SB203580 or by mutation of CREB at Ser133. pp60(v-src) induction of ATF-2 was abolished by the c-Jun N-terminal kinase inhibitor JNK-interacting protein-1 or by mutation of ATF-2 at Thr69 and Thr71. CREB and ATF-2, which bind to a common pp60(v-src) response element, are transcriptionally activated by distinct mitogen-activated protein kinases. Induction of cyclin D1 activity by pp60(v-src) may contribute to breast tumorigenesis through phosphorylation and inactivation of the retinoblastoma protein.

Activating Transcription Factor 2↗
PubMed1999

C/EBP beta in rheumatoid arthritis: correlation with inflammation, not disease specificity.

Rheumatoid arthritis synovial tissue was examined and compared with osteoarthritis tissue for the presence of the nuclear transcription factor C/EBP beta (NF-IL-6). The region (lining or sublining), cell type, and subcellular distribution (cytoplasmic or nuclear) of the expression of C/EBP beta was characterized. Rheumatoid arthritis synovial fluid and blood and normal peripheral blood were also examined. C/EBP beta was detected in the synovial lining and in sublining cells of synovial tissue from patients with both rheumatoid and osteoarthritis. A significant (P < 0.001 and < 0.05, respectively) increase in the percentage of cells with nuclear staining was seen in the lining layer, compared to cells in the sublining region, in rheumatoid and osteoarthritis. In both diseases a strong correlation (r = 0.79, P < 0.001) was observed between the percentage of cells in the synovial lining that were positive for nuclear C/EBP beta and lining cell depth. Two-color immunohistochemistry demonstrated that both macrophages and fibroblast-like synoviocytes were positive for nuclear C/EBP beta. The presence of C/EBP beta was confirmed by immunohistochemistry and Western blot analysis with isolated synovial fibroblasts. Nuclear C/EBP beta was also detected in rheumatoid synovial fluid monocytes/macrophages, but not in lymphocytes or neutrophils. Western blot analysis confirmed the presence of C/EBP beta in these cells. The intensity of C/EBP beta staining was greater (P < 0.001) in synovial fluid monocytes than in those from normal or rheumatoid peripheral blood. In conclusion, the enhanced nuclear staining for C/EBP beta in the synovial lining, compared to the sublining, suggesting activation in the lining, and the positive correlation of lining layer depth with the percentage of cells in the lining positive for nuclear C/EBP beta, suggest a potential role for C/EBP beta in chronic inflammation. The regulation of the production or activity of C/EBP beta, to inhibit inflammatory mediator expression by synovial macrophages and fibroblasts, offers a novel approach to therapeutic intervention.

Arthritis, Rheumatoid↗
PubMed1999

Nitric oxide synthase type 3 is increased in squamous hyperplasia, dysplasia, and squamous cell carcinoma of the head and neck.

The implication of nitric oxide (NO*) in the multistep process of carcinogenesis prompted us to examine the expression of endothelial constitutive nitric oxide synthase (NOS3) in head and neck squamous cell carcinoma (HNSCCa). Eleven paraffin-embedded samples of normal oral mucosa, 3 reactive oral lesions, 13 samples of squamous dysplasia, and 120 specimens of HNSCCa were immunostained with an anti-NOS3 monoclonal antibody and graded on a 0 to 4+ scale of intensity. Normal squamous mucosa demonstrated very little NOS3 expression. Areas of normal mucosa, reactive mucosa, and dysplastic lesions associated with inflammation tended to demonstrate regional expression of NOS3. Reactive mucosal lesions, squamous dysplasia, and HNSCCa demonstrated a significant (p<.0001) increase in global expression of NOS3. Therefore, NOS3 is expressed very little in histologically normal squamous mucosa, while squamous hyperplasia, dysplasia, and HNSCCa express significantly more NOS3. Regional variation in NOS3 expression appears to be associated with perilesional inflammation.

Antibodies, Monoclonal↗
PubMed1998

Regulation of cyclin dependent kinase inhibitor proteins during neonatal cerebella development.

The cyclin dependent kinase holoenzymes (CDKs), composed of catalytic (cdk) and regulatory (cyclin) subunits, promote cellular proliferation and are inhibited by cyclin dependent kinase inhibitor proteins (CDKIs). The CDKIs include the Ink4 family (p15Ink4b, p16Ink4a, p18Ink4c, p19Ink4d) and the KIP family (p21Cip1 and p27Kip1). The sustained induction of p21 and p18 during myogenesis implicates these CDKI in maintaining cellular differentiation. Herein we examined the CDK (cyclin D1, cdk5) and CDKI expression profiles during the first 24 days of postnatal rat cerebella development. Cdk5 abundance increased and cyclin D1 decreased from day 9 through to adulthood. The CDKIs increased transiently during differentiation. p27 increased 20-fold between days 4 and 24, whereas p21 rose twofold between 6 to 11 days. p19, p18 and p16 increased approximately two- to threefold, falling to low levels in the adult. Immunostaining of cyclin D1 was localized in the external granular cells, whereas p27, was found primarily in the Purkinje cells. The period of maximal differentiation between days 9 to 13 was associated with a change in p21 and p16 staining from the external granular and Purkinje cells to a primarily Purkinje cell distribution. Protein-calorie malnutrition, which was previously shown to arrest rat cerebella development, reduced cyclin D1 kinase activity and p27 levels. However, p16 and p21 levels were unchanged. We conclude that the CDKIs are induced with distinct kinetics in specific cell types and respond differentially to growth factors during cerebella development, suggesting discrete roles for these proteins in normal cerebella development.

Animals↗
PubMed1998

Endothelial constitutive nitric oxide synthase (ecNOS) localization in normal and neoplastic salivary tissue.

BACKGROUND: Nitric oxide (NO.) has been implicated in the process of carcinogenesis in various organs. This study was designed to investigate the expression of endothelial constitutive nitric oxide synthase (ecNOS) in normal and neoplastic salivary tissues. METHODS: Paraffin-embedded tissue from 48 salivary tumors and adjacent non-neoplastic tissue was immunohistochemically evaluated for both frequency (percentage) and intensity (1-4+) of staining using a commercially available anti-ecNOS monoclonal antibody. RESULTS: Expression of ecNOS was predominantly localized to vascular endothelium, skeletal muscle, and to salivary duct luminal epithelium in normal salivary tissue (n = 37). All salivary tumors demonstrated at least 1 + cytoplasmic staining for ecNOS without apparent correlation to most clinical parameters. A tendency toward increased frequency and intensity of ecNOS expression in oncocytic cells, relative to cells with myoepithelial or acinar differentiation, was noted. CONCLUSIONS: Expression of ecNOS is localized to the luminal cells of normal salivary ducts. Limited expression of ecNOS was found in all the salivary gland tumors examined. This suggests a common histogenesis for this diverse group of tumors, which may reflect different degrees of differentiation toward luminal duct epithelium. The possible role of ecNOS and NO. in salivary gland carcinogenesis is intriguing and warrants further study.

Adult↗
PubMed1998

Effects of thrombospondin-1 on disease course and angiogenesis in rat adjuvant-induced arthritis.

Leukocyte extravasation into the synovium is important in rheumatoid arthritis (RA). Thrombospondin (TSP)-1 mediates cell adhesion and migration and inhibits angiogenesis, and it has been implicated in RA. However, little information is available on the role of TSP-1 in arthritis-associated inflammation and neovascularization. Therefore, we analyzed the effects of TSP-1 in adjuvant-induced arthritis (AIA), a rat model for RA. Hydron pellets containing TSP-1 were implanted in one ankle of AIA rats post-adjuvant injection, while the contralateral ankle received sham implants. Body weight loss and joint swelling were determined in comparison to nonimplanted AIA controls. In addition, synovial vessel counts were obtained in TSP-1-versus sham-implanted ankles of the same rat. The implantation of TSP-1 pellets into one ankle resulted in an enhancement of swelling in both ankles. Furthermore, TSP-1 exhibited a biphasic modulatory effect on synovial vessel counts (P < 0.05). In conclusion, TSP-1 implanted into one ankle of AIA rats may augment the severity of the disease. One possible explanation, among others, for the modulating effect of TSP-1 on inflammation may be its effect on arthritis-related angiogenesis.

Animals↗
PubMed1998

RANTES expression and contribution to monocyte chemotaxis in arthritis.

Rheumatoid arthritis (RA) is characterized by recruitment of leukocytes from the vasculature into inflamed synovial tissue (ST) and synovial fluid (SF), which depends, in part, upon the continued maintenance of chemotactic stimuli. RANTES is a potent chemoattractant for leukocytes including monocytes and CD45RO+ memory T lymphocytes. The aim of this study was to determine the production, the source, and the function of antigenic RANTES in arthritis. We detected antigenic RANTES in SFs from RA and OA patients (100 +/- 22.7 and 72 +/- 30.7 pg/ml, respectively). CM from RA ST fibroblasts stimulated with interleukin-1beta or tumor necrosis factor-alpha contained significantly more antigenic RANTES than unstimulated CM (452 +/- 181.6 and 581 +/- 200.2 pg/ml, respectively, versus 12 +/- 4.4 pg/ml, P < 0.05). PHA-stimulated RA SF mononuclear cells secreted 5- to 15-fold more antigenic RANTES than did nonstimulated mononuclear cells, while LPS induced secretion up to 4-fold. We immunolocalized antigenic RANTES to sublining macrophages (28 +/- 3.7 and 8 +/- 2.0% immunopositive cells), perivascular macrophages (56 +/- 6.9 and 19 +/- 3.4%), and synovial lining cells (37 +/- 5.8 and 60 +/- 10.4%) in RA and OA tissue, respectively. Anti-RANTES neutralized 20.2 +/- 1.3% of the RA SF chemotactic activity for normal peripheral blood monocytes (P < 0.05). These results demonstrate antigenic RANTES in RA and OA ST and SF and identify RANTES as a chemoattractant for monocytes in the RA joint.

Antigens↗
PubMed1998

Expression of p68 protein kinase and its prognostic significance during IFN-alpha therapy in patients with carcinoid tumours.

The aim of this study was to evaluate the antiproliferative effects of interferon alpha (IFN-alpha) on neuroendocrine differentiated cell lines and, retrospectively, to assess the prognostic significance of p68 protein kinase (PKR) induction in neuroendocrine gut and pancreatic tumour patients. Archive specimens from 56 patients were studied, 43 before IFN-alpha and 56 during therapy. The tissues were immunostained for p68 protein kinase (PKR) using the monoclonal antibody (MAb) TJ4C4. A significant increase in immunostaining after treatment with IFN-alpha compared with before treatment (3.47 +/- 0.12 versus 2.72 +/- 0.15, P < 0.001) was noted. The p68 score was significantly increased after treatment only in patients with stable disease before = 2.71 +/- 0.19, after = 3.40 +/- 0.14 (P < 0.001) or an objective response before 3.13 +/- 0.22, after = 4.00 +/- 0.24 (P < 0.05) but not in those with progressive disease (before = 2.32 +/- 0.24, after 2.86 +/- 0.26, NS). A low p68 score (< 3.0) during treatment was a predictor of shorter duration of response and overall survival (P = 0.0062 and P < 0.0001, respectively). Furthermore, IFN-alpha showed a significant antiproliferative effect (by [3H]thymidine incorporation) on two carcinoid tumour cell lines in a dose-dependent manner which correlated with a dose-dependent induction of p68 mRNA and protein expression (by Northern and Western blot analysis). We conclude that IFN-alpha can effectively inhibit the in vitro growth of carcinoid tumor cell lines and upregulates the expression of p68 at both mRNA and protein levels in carcinoid tumours. The induction of p68 could be a prognostic indicator of response in patients with carcinoid tumours during IFN-alpha treatment.

Antineoplastic Agents↗
PubMed1998

Heterogeneity of microsatellite mutations within and between loci, and implications for human demographic histories.

Microsatellites have been widely used to reconstruct human evolution. However, the efficient use of these markers relies on information regarding the process producing the observed variation. Here, we present a novel approach to the locus-by-locus characterization of this process. By analyzing somatic mutations in cancer patients, we estimated the distributions of mutation size for each of 20 loci. The same loci were then typed in three ethnically diverse population samples. The generalized stepwise mutation model was used to test the predicted relationship between population and mutation parameters under two demographic scenarios: constant population size and rapid expansion. The agreement between the observed and expected relationship between population and mutation parameters, even when the latter are estimated in cancer patients, confirms that somatic mutations may be useful for investigating the process underlying population variation. Estimated distributions of mutation size differ substantially amongst loci, and mutations of more than one repeat unit are common. A new statistic, the normalized population variance, is introduced for multilocus estimation of demographic parameters, and for testing demographic scenarios. The observed population variation is not consistent with a constant population size. Time estimates of the putative population expansion are in agreement with those obtained by other methods.

Adenocarcinoma↗
PubMed1998

Interferon-responsive protein kinase (p68) and proliferating cell nuclear antigen are inversely distributed in head and neck squamous cell carcinoma.

PKR (protein kinase, interferon-responsive) is a ribosomal-associated protein kinase found in all human cells. When activated by dsRNA or polyanionic substances, PKR efficiently inhibits cellular protein synthesis. PKR expression has been correlated with cellular differentiation in a number of tumor types, including squamous cell carcinoma of the head and neck region. Although transfection of PKR into mouse fibroblasts and yeast cells inhibits proliferation, it is not known if modulation of native PKR levels occurs during cellular proliferation and differentiation in human normal and neoplastic tissues. To determine whether PKR expression was inversely related to proliferative activity in vivo, we used double-label immunohistochemistry to colocalize PKR and the proliferation marker, proliferating cell nuclear antigen (PCNA), in a series of head and neck squamous cell carcinomas. Overall, neoplasms demonstrating high levels of PKR showed low levels of PCNA immunoreactivity; carcinomas with low levels of PKR expressed high levels of PCNA. Within individual tumors, PKR and PCNA showed an inverse regional distribution: PKR was located predominantly in the center of tumor nests, while PCNA was restricted to the periphery. Patients whose tumors expressed high levels of both PKR and PCNA had the longest mean disease-free survival. These findings support the hypothesis that PKR levels are modulated in cell proliferation and differentiation in head and neck squamous cell carcinoma. Further studies are needed to clarify the mechanisms underlying the antiproliferative activity of PKR.

Adult↗
PubMed1998

Expression of the adenocarcinoma-related antigen recognized by monoclonal antibody 44-3A6 in salivary gland neoplasias.

The monoclonal antibody 44-3A6 detects a cell-surface protein that has been shown to be a useful marker in distinguishing adenocarcinomas from other histologic tumor types in a variety of tissues. The objective of this study was to determine whether 44-3A6 could be used as a tool in the classification of salivary gland neoplasms. These complex tumors share overlapping pathologic features but distinct clinical outcomes. This study used 44-3A6 to immunohistochemically describe the pattern and frequency of this antigen in salivary gland neoplasms. Formalin-fixed, paraffin-embedded tissue sections of 22 benign and 26 malignant salivary tumors were evaluated. The patient population consisted of 25 (52.1%) women and 23 (47.9%) men selected from archival pathology files to reflect a range of salivary gland diseases. Normal surrounding salivary glands were found to have intense focal staining almost exclusively localized to ductal luminal cells. There was little staining of either myoepithelial or acinar cells. A wide spectrum of expression was found between and within tumor types, but a trend toward more expression of this antigen with decreasing differentiation was seen. A significant increase in staining was also seen in those tumors with ductal differentiation (n = 41) as opposed to those with predominantly acinar (i.e., acinic cell carcinoma) or myoepithelial (i.e., myoepithelioma; n = 8) differentiation (2.6 vs. 1.3, p < 0.05). No correlation was found between staining intensity and facial paralysis, pain, skin involvement, TNM stage, residual disease, or disease-free or total survival. Therefore this antigen appears to designate a duct luminal phenotype in normal and neoplastic salivary tissues.

Adenocarcinoma↗
PubMed1997

Low-level production of interleukin-13 in synovial fluid and tissue from patients with arthritis.

Rheumatoid arthritis (RA) is a chronic, aggressive disease characterized by inflammatory cells in the synovial tissue (ST) and synovial fluid (SF). Interleukin (IL)-13 inhibits the production of proinflammatory cytokines, chemokines, and hematopoietic growth factors by activated human monocytes. The aim of this study was to determine the production of IL-13 in various forms of arthritis. The presence of IL-13 in RA was found to be low, in that 18 of 26 RA SF samples and 10 of 14 RA peripheral blood (PB) samples had nondetectable levels (</=12 pg/ml). Similar low levels were found in SF and PB from patients with osteoarthritis (OA) and other arthritides. In contrast, RANTES, IL-8, monocyte chemotactic protein-1, and soluble P-selectin were found at levels of 13-, 120-, 1200-, and 2000-fold excess of IL-13, respectively. Mononuclear cells isolated from RA SFs did not produce significant levels of IL-13 in culture (</=12 pg/ml) but were able to do so when stimulated with phytohemagglutinin. Likewise, tissue explants from RA synovium cultured for 24 or 48 hr with or without serum did not produce appreciable quantities of IL-13 (</=12 pg/ml). Immunohistochemical data were in accordance with this result in that antigenic IL-13 was not detected on the majority of RA, OA, and normal (NL) ST cells. These results demonstrate a paucity of IL-13 within the joints of RA, OA, NL, and other arthritic patients by comparison with levels of other cytokines.

Arthritis↗
PubMed1997

Differential expression of the urokinase receptor (CD87) in arthritic and normal synovial tissues.

AIM: To determine whether the urokinase plasminogen activator receptor (u-PAR; CD87) exhibits a possible pathogenic role in rheumatoid and osteoarthritis. METHODS: A semiquantitative, indirect immunoperoxidase histochemical analysis was performed on frozen synovial tissue sections. The recently characterised monoclonal antibody 10G7 recognising transfectants bearing u-PAR was used. Synovial tissue was obtained from 10 patients with rheumatoid arthritis, 10 patients with osteoarthritis, and four normal subjects. RESULTS: u-PAR was expressed on 70-90% of synovial tissue lining cells and subsynovial, interstitial macrophages from the arthritis patients, but only on a few myeloid cells from the normal subjects. It was also present on more endothelial cells from the rheumatoid and osteoarthritis patients, than from normal synovial tissue. CONCLUSIONS: Plasminogen activators are important in joint destruction underlying arthritis. The up-regulated expression of u-PAR in diseased versus normal synovial tissue suggests a role for this antigen in the inflammatory and angiogenic mechanisms underlying rheumatoid and osteoarthritis.

Arthritis, Rheumatoid↗
PubMed1997

Cytoplasmic localization of endothelial constitutive nitric oxide synthase in endometrial carcinomas.

BACKGROUND: Production of nitric oxide by nitric oxide synthase (NOS) has been implicated in numerous physiologic and pathophysiologic processes including mutagenesis. This study was designed to examine the expression of the endothelial constitutive isoform of NOS (ecNOS) in endometrial carcinomas. METHODS: Fifty endometrial carcinomas (42 endometrioid, 4 serous papillary, 2 clear cell, and 2 adenosquamous carcinomas) and 21 normal endometrial gland tissue specimens (5 cases of proliferative, 5 early secretory, 5 mid-secretory, and 5 late secretory and 1 menstrual phase endometrium), previously formalin fixed and paraffin embedded, were immunostained using a commercially available anti-ecNOS monoclonal antibody. Localization of ecNOS staining to the plasma membrane, cytoplasm and nuclei was graded with respect to overall staining intensity (0-3+ scale) and frequency (percentage of immunoreactive cells). RESULTS: Relatively little staining for ecNOS was localized to the plasma membrane in either normal or neoplastic tissues. Normal and hyperplastic endometrial glands demonstrated moderate cytoplasmic and weak nuclear staining in a small percentage of cells. While ecNOS expression was most prominent in epithelial cells, weak expression was also rarely noted in endometrial stroma, blood vessel walls, and endothelium. We found a broad range of ecNOS expression in endometrial carcinomas, predominantly localized to the cytoplasm and nuclei. No statistically significant difference in ecNOS staining frequency or intensity was found between different histologic subtypes of endometrial carcinomas. No apparent correlation was found between ecNOS expression and tumor stage, grade, extension to the lower uterine segment or cervix, nodal or distant metastases, recurrence, or final patient status among patients with endometrioid adenocarcinomas. Endometrioid tumors invading more than 1/2 of myometrial thickness (n = 18) had significantly higher cytoplasmic staining intensity than those tumors limited to the inner 1/2 of myometrium (n = 27; 2.0 vs. 1.3, p < 0.04). Furthermore, a trend toward shorter disease-free survival was noted with increased staining intensity and decreased staining frequency. CONCLUSIONS: Cytoplasmic and nuclear expression of ecNOS, which is primarily limited to the glandular elements of normal endometrium, is also found to be expressed in endometrial carcinoma. Increased ecNOS staining intensity and decreased frequency tends to correlate with decreased disease-free survival. Lastly, increased cytoplasmic ecNOS staining intensity correlates with increased myometrial invasion.

Adult↗
PubMed1996

Cellular adhesion molecules in rat adjuvant arthritis.

OBJECTIVE: To examine adhesion molecule expression during the progression of inflammation in a rheumatoid arthritis model of adjuvant-induced arthritis (AIA) in rats. METHODS: Immunohistochemical analysis was used to determine the distribution of the following adhesion molecules: lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18), Mac-1 and p150/95 (CD11bc/CD18), intercellular adhesion molecule 1 (ICAM-1), and CD44 in tissue sections from the ankle joints of rats with AIA. Control animals and those with AIA were killed at intervals over a 54-day period after injection with mineral oil and Mycobacterium butyricum, respectively. RESULTS: CD44 and LFA-1 were expressed on lymphocytes, macrophages, and synovial (ST) lining cells. CD44 expression on macrophages was found to be increased compared with control animals by day 18, and was significantly increased by day 41. CD44 expression on lymphocytes significantly increased earlier, on days 11-18. Increased LFA-1 expression on macrophages occurred late, on day 41. LFA-1 expression on lymphocytes was significantly increased on days 25, 47, and 54. ST lining cells exhibited two distinct periods of increased expression, one early, on days 11-25 and one later, on days 41-54. CD11b/c was expressed on macrophages and ST lining cells, showing a significant increase on AIA rat ST lining cells compared with control animals on day 4. No differences in ICAM-1 expression on endothelial cells between rats with AIA and controls were found on any of the days examined. CONCLUSION: CD44 expression is up-regulated on macrophages and lymphocytes during the early development of AIA, while LFA-1 expression is up-regulated later in the development of AIA. The up-regulation of CD44 and LFA-1 at different times in the development of AIA suggests an important role for these adhesion molecules in establishing and sustaining an inflammatory response in the AIA joint.

Animals↗
PubMed1996

Hepatocyte growth factor. A cytokine mediating endothelial migration in inflammatory arthritis.

OBJECTIVE: Angiogenesis is an integral component of the vasculoproliferative phase of rheumatoid arthritis (RA). Recently, a heparin-binding cytokine termed hepatocyte growth factor (HGF), or scatter factor (due to its ability to disperse cohesive epithelial colonies), was described. We conducted this study to investigate the hypothesis that this cytokine was present in the milieu of the inflamed joint, and that it contributed to the chemotaxis of endothelial cells in the synovial tissue. METHODS: We examined synovial fluid, synovial tissue, and peripheral blood from 91 patients with RA and other arthritides. We used 83 total samples in an enzyme-linked immunosorbent assay to quantitate the HGF in synovial fluids and peripheral blood. To determine whether the HGF was biologically active, an epithelial scatter factor assay was performed. Immunohistochemical analysis was used to determine localization in synovial tissues. To define a function for synovial HGF, we preincubated rheumatoid synovial fluids with neutralizing anti-HGF and measured the ability of these synovial fluids to induce endothelial chemotaxis. RESULTS: Synovial fluid from patients with RA contained a mean +/- SEM HGF concentration of 2.0 +/- 0.3 ng/ml, while synovial fluid from patients with other arthritides (including inflammatory arthritis) contained 2.4 +/- 0.7 ng/ml HGF. Osteoarthritis (OA) patient samples contained the smallest quantities of synovial fluid HGF at 0.9 +/- 0.1 ng/ml. RA synovial fluid contained significantly more HGF than did RA peripheral blood (1.1 +/- 0.2 ng/ml) (P < 0.05). Rheumatoid synovial fluids induced more scattering of cells than did OA synovial fluids, suggesting a role for this cytokine in rheumatoid joint destruction. Interleukin-1 beta induced expression of rheumatoid synovial tissue fibroblast antigenic HGF and scatter factor activity. Immunohistochemically, HGF, as well as the HGF receptor (the met gene product), localized to significantly more rheumatoid synovial tissue lining cells than normal lining cells (P < 0.05). Both HGF and its receptor immunolocalized to subsynovial macrophages as well. Levels of synovial tissue immunoreactive HGF correlated positively with the number of synovial tissue blood vessels. Anti-HGF neutralized a mean of 24% of the chemotactic activity for endothelial cells found in 10 rheumatoid synovial fluid samples. CONCLUSION: These results indicate that synovial HGF may contribute to the vasculoproliferative phase of inflammatory arthritides such as RA, by inducing HGF-mediated synovial neovascularization. These findings point to a newly described role for HGF in the fibroproliferative phase of RA-associated synovitis.

Arthritis, Rheumatoid↗