(Circulation. 1995;92:1487-1493.)
© 1995 American Heart Association, Inc.
Articles |
Expression and Functional Significance of Tumor Necrosis Factor Receptors in Human Myocardium
From the Cardiology Section (G.T.-A., S.K., J.L., R.L., D.L.M.), Departments of Medicine and Pathology, Veterans Administration Medical Center and Baylor College of Medicine, Houston, Tex; and the Cardiology Section (R.D.B.), Department of Medicine, University of Colorado (Denver).
Correspondence to Douglas L. Mann, MD, Cardiology Section, VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Tumor necrosis factor–
(TNF-), a
proinflammatory cytokine with potent negative inotropic
properties, is elaborated in septic shock, acute myocarditis,
reperfusion injury, and congestive heart failure. TNF- acts by
binding to two specific receptors: TNFR1 and TNFR2. However, neither
the presence nor the significance of TNF receptors has been studied in
the adult mammalian heart.
Methods and Results In the present study, we showed that the
adult heart expresses mRNA and receptor proteins for TNFR1 and TNFR2.
Moreover, immunohistochemical staining studies localized TNFR1 and
TNFR2 to the cardiac myocyte, providing a potential signaling pathway
for the deleterious effects of TNF-. The functional significance of
the expression of TNFR1 and TNFR2 was explored with the use of a simple
cell motion assay in which we assessed the effect(s) of TNF- mutants
known to bind selectively to human TNFR1 and TNFR2. We showed that the
negative inotropic effect of wild-type TNF- in isolated feline
cardiac myocytes was mimicked by the TNF mutant that binds to TNFR1,
whereas the TNF mutant that binds to TNFR2 had no significant effect on
cell motion.
Conclusions Results of the present study show that the adult
human heart expresses both mRNA and receptor proteins for TNFR1 and
TNFR2; moreover, the negative inotropic effects of TNF- in adult
cardiac myocytes appear to be initiated by activation of TNFR1.
Key Words: tumor necrosis factor • myocardium • myocytes
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Tumor necrosis factor–
(TNF-) was
originally discovered as a protein that produced necrotizing effects in
certain types of transplantable mouse tumors.1 Subsequent
studies have shown that the spectrum of biological activities for
TNF- is not limited to cytotoxic effects but rather that TNF-
exerts pleiotropic effects in a wide variety of mammalian cell types,
including adult cardiac myocytes.2 3 4
Although the precise
role of TNF- in the heart is not known, the elaboration of TNF-
in cardiac pathophysiological contexts in which
left ventricular dysfunction develops, such as septic
shock, myocarditis, cardiac allograft rejection, and congestive heart
failure,5 6 7 8 9 10 11
suggests that TNF- may play a pathogenetic
role in these disease states. However, the basic cellular and molecular
mechanisms responsible for signaling the negative inotropic effects of
TNF- are not known.
TNF- initiates its biological effects by binding to two distinct
cell surface receptors with approximate molecular masses of 55 kd
(TNFR1) and 75 kd (TNFR2). Although both TNF receptor species have been
cloned in humans12 13 14 15
and are believed to be expressed
widely in mammalian cells,16 17 it is not known
whether
they are expressed in the adult heart. Accordingly, the purpose of the
present study was to determine whether TNF- receptors are
expressed in the adult human heart as well as to determine their
functional significance. In the present study, we showed that the
human heart expresses both mRNA and receptor proteins for TNFR1 and
TNFR2. Moreover, results from the present study suggest that the
negative inotropic effects of TNF- are initiated by activation of
TNFR1.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Tissue Procurement
Myocardial samples were obtained from organ donors (mean age, 32.2±7.8 years) whose hearts were initially considered for cardiac transplantation but were subsequently deemed unsuitable for transplantation because of blood type or size incompatibility (Table 1
). There was no history of primary myocardial disease or
evidence of
active infection or malignancy in these patients before explantation.
All organ donors had normal left function as documented by
two-dimensional echocardiography. Moreover,
trabeculae isolated from the right ventricles of these
subjects demonstrated normal rates of force development and normal
levels of peak tension at baseline and after the administration of
isoproterenol.18 19 Immediately after elective
cardiac
explantation, tissue aliquots from the still-beating heart were
immediately frozen in liquid nitrogen and stored at -80°C until
analysis.
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Myocardial TNF Receptors
Myocardial TNF Receptor Gene
Expression
Total RNA was extracted from normal myocardium by
the guanidinium thiocyanate method.20 Total RNA was
denatured at 65°C for 10 minutes, size-fractionated on a 1% agarose
gel containing 2.2 mol/L formaldehyde (10 µg/lane), transferred onto
nylon membrane (GeneScreen, Dupont NEN), and hybridized sequentially to
random primed cDNA probes.20 The following probes were
used for Northern blot analysis: a 1.0-kb EcoR1
fragment of the human TNFR1 (a gift from C. Smith, Immunex); a 0.64-kb
Not I/Bgl I fragment of the human TNFR2 (a gift
from C. Smith, Immunex); and a 0.5-kb Xba
I/HindIII fragment of human
glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which
was used as an internal control. The membranes were washed once with
standard saline citrate and 0.1% sodium dodecyl sulfate at
55°C for 30 minutes, air dried, and exposed to Kodak X-Omat A film at
-70°C.
Myocardial TNF Receptor Proteins
Frozen sections of myocardium were cut into 0.5- to
1.0-g pieces, suspended in a phosphate-buffered saline (PBS) solution
containing protease inhibitors (1.49 mmol/L
phenylmethylsulfonyl fluoride, 475.6 µmol/L leupeptin, and
0.31 µmol/L aprotinin), and homogenized for 30 to 60
seconds with a Polytron PT-3000 (Brinkman Instruments). The myocardial
homogenates were centrifuged for 20 minutes at
4°C at 20 000g. The resultant cell pellet was solubilized
according to the method of Stauber et al.21 Briefly, the
cell pellet was resuspended in PBS with proteinase
inhibitors and 1% Triton X-100. The pellet was incubated
for 1 hour at 4°C, and the solubilized proteins were
centrifuged for 20 minutes at 20 000g at 4°C to
remove particulate debris. The supernatant, which contained the
solubilized cell membrane–bound TNF receptor,21 was used
for analysis of TNFR1 and TNFR2. The protein content of the
membrane fraction was determined with a commercially available assay
(BCA, Pierce), with bovine serum albumin as a standard.
Levels of TNFR1
and TNFR2 in the membrane fraction were measured with a
"sandwich" ELISA, with commercially available kits used for the
detection of human TNFR1 and TNFR2 (Quantikine, R&D Systems). The
antibodies used in these immunoassays have been characterized
extensively for specificity by the suppliers, are not influenced
adversely by the presence of TNF- or TNF-ß, and have a lower limit
of detection of 7.8 pg/mL for both receptors. Briefly, 1.3±0.1 mg/mL
of solubilized myocardial membrane protein was diluted 1:5 in
"calibrator diluent"; 200 µL of unknown sample was then added
to each well along with the appropriate recombinant human soluble TNFR1
and TNFR2 standards, and the immunoassay was performed exactly
according to the manufacturer's suggestions. After the addition of
substrate, results were analyzed spectrophotometrically at a
wavelength of 450 nm with a microtiter plate reader. Results were
expressed as picomoles per liter of TNF receptor per gram of membrane
protein and represent the mean value of two separate
measurements performed in duplicate.
Two preliminary control studies were performed to validate the ELISA technique for quantifying membrane-bound proteins. First, to confirm that the homogenizing buffer (used to solubilize the membrane fraction) did not adversely influence the ability of the ELISA to detect solubilized TNFR1 and TNFR2, we diluted purified recombinant TNFR1 (148 pmol/L) and TNFR2 (156 pmol/L) with either homogenizing buffer or "assay diluent"; there was no difference in the immunodetectable levels of TNFR1 or TNFR2 obtained with homogenization buffer compared with the levels obtained with assay diluent. Second, we examined the ability of this method to detect levels of TNFR1 and TNFR2 in two human cell lines known to express high levels of TNFR2: U-937 cells (a histiocytic leukemia cell line) and peripheral blood mononuclear cells. These control studies showed that the ratio of TNFR2 to TNFR1 was 2.6 and 1.8 for U-937 cells and monocytes, respectively, which is similar to that reported in the literature for ligand-binding assays.22 23
Immunolocalization of
TNF Receptors
Immunostaining of human myocardial samples for
TNFR1 and TNFR2 was performed using a modification of the method
described by Yelavarthi and Hunt24 for immunolocalizing
TNF receptors in human placenta. Briefly, serial sections of
myocardium were incubated with nonimmune rabbit serum or
polyclonal rabbit antibody (1:50 dilution) against TNFR1 (provided by
C. Smith, Immunex) or polyclonal rabbit antibody (1:100 dilution)
against TNFR2 (provided by C. Smith, Immunex). The primary antibodies
used have been characterized extensively by the provider and do not
cross-react between TNF receptor subtypes. Myocardial sections were
incubated for 16 to 18 hours, washed three times in PBS, and then
incubated for 45 minutes with a biotinylated anti-rabbit antibody
(diluted 1:100). The tissue sections were then washed three times in
PBS and developed with a commercially available kit (BioGenex) that
uses alkaline phosphatase as the enzyme label and Fast Red
(4-chloro-2-methyl-benzene-diasonium chloride naphalene disulfonate) as
the chromogen substrate.
Functional Analysis of TNF
Receptors
To examine the functional significance of TNF receptors in
the
cardiac myocytes, we used a simple cell motion assay3 to
characterize the effects of two "TNF- mutants." These mutated
ligands have double-point mutations in their TNF receptor binding
domains,25 such that they have specificity for binding to
either human TNFR1 (corresponding mutant TNFM1; provided by W.
Lesslauer, F. Hoffman–La Roche25 ) or to TNFR2
(corresponding mutant TNFM2; provided by W. Lesslauer, F. Hoffman–La
Roche25 ). The double-point mutation in the TNFM1 mutant
results in a minimal effect on the affinity of TNFM1 for TNFR1, whereas
binding to TNFR2 is 1000-fold less. Similarly, the double-point
mutation in the TNFM2 mutant results in a minimal effect on the
affinity of TNFM2 for TNFR2, whereas binding to TNFR1 is 2500-fold
less.25 Isolated feline cardiac myocytes were used to
assess the effects of the TNF- mutants for two reasons: first, the
mechanical and electrophysiological
properties of feline myocardium are similar to those of
human subjects,26 and second, it was not practical to
obtain calcium-tolerant human cardiac myocytes from normal human hearts
on a routine basis.
Cell motion was characterized with video edge
detection as we have
previously described in detail.3 Freshly isolated myocytes
were treated for 30 minutes at 37°C with a single concentration of
recombinant human TNF- (Genzyme) that is known to produce negative
inotropic effects in isolated cardiac myocytes (0.1 nmol/L [200
U/mL3]) or a range of concentrations of TNFM1 (0.1 to 10
nmol/L), of TNFM2 (0.1 to 10 nmol/L), or a combination of TNFM1 (0.1
nmol/L) and TNFM2 (0.1 nmol/L, 10 nmol/L). Control cells were treated
with an equal volume of diluent (10 mL/L [1%] of endotoxin-free
human serum albumin). Results were expressed as the percentage
change in cell length from resting values.27
To confirm
that the human TNF- mutants were capable of binding to
TNF receptors in feline cardiac myocytes, we performed competition
binding assays with the TNF- mutants using a modification of the
method of Baglioni et al.28 Briefly, 5x103
freshly isolated cardiac myocytes were plated in 96-well plates in 200
µL of binding medium (Hanks' balanced salt solution supplemented
with 50 mL/L [5%] fetal calf serum). The cells were incubated for 6
hours28 at 4°C with 1 nmol/L of
125I–TNF- in the presence of diluent, TNFM1 (60
nmol/L), or TNFM2 (60 nmol/L).28 The myocytes were then
removed from the plates and centrifuged at 20 000g
for 2 minutes through phthalate mix (80% dibutyl phthalate oil, 20%
olive oil) to separate bound from unbound 125I–TNF-.
The gamma emissions in the resultant cell pellets and supernatants were
then determined. The amount of 125I–TNF- binding to the
cardiac myocytes was determined in the presence and absence of TNF-
mutant ligands. Results for TNFM1 and TNFM2 were expressed as the
percentage of total 125I–TNF- binding, which was
obtained in cells studied in the absence of a competing ligand. In
control experiments (see "Appendix"), we confirmed the
specificity of binding of the human TNF- mutants to feline TNFR1 and
TNFR2.
Statistical Analysis
Each value is expressed as
mean±SEM. One-way ANOVA was used to
test for mean differences in cell shortening after treatment with
TNF- or TNFM1 or TNFM2 mutants; where appropriate, post hoc multiple
comparison testing was performed to test for differences between
control and experimental groups (Dunnett's test) or between different
experimental groups (Newman-Keuls). Significant differences were said
to exist at P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Myocardial TNF Receptors
TNF Receptor Gene Expression
Fig 1
shows a representative
Northern blot of mRNA from three normal hearts with cDNA probes for
human TNFR1 and TNFR2 and GAPDH. As shown, mRNA for both TNFR1 and
TNFR2 was detected in each of the normal myocardial samples. Similar
findings with respect to the gene expression for TNFR1 and TNFR2 were
observed in the remaining two samples of normal human
myocardium.
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TNF Receptor Protein
Fig
2 shows the results of the TNFR1 and TNFR2
receptor protein assays in isolated membranes from whole heart
homogenates of normal myocardium (n=5). As
shown, both TNFR receptor subtypes were easily detected in solubilized
human cardiac sarcolemmal preparations by receptor subtype–specific
ELISA.
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Immunolocalization of TNF Receptors
Fig
3A depicts the immunostaining
pattern for normal myocardium with nonimmune rabbit sera
(control) as the primary antibody, followed by a biotinylated goat
anti-rabbit antibody. As shown, immunostaining with
alkaline phosphatase was not observed when nonimmune serum was used.
Fig 3B and 3C depicts the immunohistochemical
staining patterns for
normal human myocardium stained with anti-human TNFR1 and
TNFR2 antibodies, respectively. The relevant finding is that the
pattern of immunolocalization was similar for TNFR1 and TNFR2; that is,
the immunostaining pattern for both receptors was
localized to the cardiac myocytes. Histochemical analysis of
other cell types in the myocardium revealed
immunostaining of vascular smooth muscle cells, as well
as the luminal border of vascular endothelial cells. In
subsequent studies with monoclonal antibodies directed against TNFR1
and TNFR2, an identical staining pattern was obtained.
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Functional Assessment of TNF Receptors
The salient finding
shown in Fig 4A is that the
negative inotropic effects of wild-type TNF- were mimicked by the
TNF- mutant that binds to TNFR1 (TNFM1), whereas the TNF- mutant
that binds to TNFR2 (TNFM2) had no significant effect on cell motion,
despite the use of a broad range of concentrations of the TNFM2 ligand
(0.1 to 10 nmol/L). To test the possibility that TNFR1 might supply a
cosignal that was necessary for TNFR2 to transduce negative inotropic
effects, we stimulated the myocytes simultaneously with
TNFM1 and TNFM2. Fig 4A (right) shows that simultaneous
stimulation of the myocytes with TNFM1 (0.1 nmol/L) and TNFM2 (0.1
nmol/L, 10 nmol/L) did not produce a greater depression of cell
shortening than was observed with stimulation with TNFM1 (0.1 nmol/L)
alone. ANOVA indicated that there were overall significant differences
in the extent of cell shortening between groups (P<.001);
post hoc ANOVA testing (Dunnett's) indicated that there were
significant differences from control (P<.05) values for
wild-type TNF- and for each concentration of the TNFM1 tested,
whereas values for TNFM2 were not significantly different
(P>.05) from control. Furthermore, there was no significant
difference (P>.05 [Newman-Keuls]) in the extent of cell
shortening among groups when the results for stimulation with TNFM1
alone (0.1 nmol/L) were compared with results for
simultaneous stimulation with TNFM1 (0.1 nmol/L) and TNFM2
(0.1 nmol/L, 10 nmol/L).
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To confirm binding of the TNF- mutants to
feline myocyte TNF
receptors, competition binding assays were performed. Fig 4B
shows that
both TNF- mutants were able to compete with wild-type
125I–TNF- for binding to isolated feline cardiac
myocytes, as demonstrated by the decrease in 125I–TNF-
binding in the myocytes incubated with either TNFM1 (61.4±2.5% of
control) or TNFM2 (46.7±4.5% of control).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study shows that the adult human myocardium expresses both subtypes of TNF receptor: TNFR1 and TNFR2. Three separate lines of evidence support this statement. First, Northern blot analysis demonstrated TNFR1 and TNFR2 mRNA (Fig 1
) in normal human myocardial samples. Second, both TNF
receptor
protein subtypes were easily detected in solubilized normal human
cardiac sarcolemmal preparations by receptor subtype–specific ELISA
(Fig 2). Third, immunohistochemical staining demonstrated the
presence
of TNFR1 and TNFR2 on the cardiac myocytes
themselves.3 6 29 Although we are aware
of one review that
suggests that the myocardium binds radiolabeled
TNF-,30 we are unaware of previous reports that have
delineated the specific presence of TNF receptors in adult cardiac
myocytes. Thus, the demonstration of TNFR1 and TNFR2 on the cardiac
myocytes provides a potential signaling pathway for the well-recognized
deleterious negative inotropic effects of
TNF-.9 29 31
However, although these studies were performed on myocardial samples
from "normal" subjects with preserved left
ventricular function (Table), we cannot
exclude the possibility that the relative abundance of TNFR1 or TNFR2
mRNA and/or protein expression might have been influenced by changes in
autonomic nervous system tone and/or other factors that might influence
the activity of cytokines or the expression of their
receptors.
A second major finding of the present study was that the negative
inotropic effects of wild-type TNF- were mimicked by a TNF-
mutant that binds to TNFR1, whereas stimulation of cardiac myocytes
with the TNF- mutant that binds TNFR2 had no significant effect on
cell motion. To test the possibility that TNFR1 might supply a cosignal
that was necessary for TNFR2 to transduce negative inotropic effects,
we simultaneously stimulated the myocytes with TNFM1 and
TNFM2. However, simultaneous stimulation of the myocytes
with TNFM1 and TNFM2 did not produce a greater depression of cell
shortening than was observed with TNFM1 alone. Thus, taken together,
these results suggest that the negative inotropic effects of TNF-
are mediated by TNFR1, with little or no signaling contribution from
TNFR2. Although we are unaware of a previous report that has
characterized the effects of TNFR1 and TNFR2 on cardiac myocyte
contractility, several recent indirect lines of
evidence support the potential importance of TNFR1 in signaling the
negative inotropic effects of TNF-. That is, previous studies in
TNFR1-deficient transgenic mice have shown that these animals are
resistant to the toxic effects of systemic
TNF-32 as well as to the systemic toxicity of
lipopolysaccharide or Staphylococcus aureus
enterotoxin B.32 33 In contrast, comparable studies
in
TNFR2-deficient mice showed that although these animals were less
sensitive to the toxic effects of systemic TNF-, they were not
completely resistant to the deleterious effects of TNF- as
were the TNFR1-deficient mice.34 These latter findings
have been interpreted as suggesting that TNFR2 "contributes" to
TNF- toxicity by recruiting TNF- for interaction with TNFR1. This
so-called "ligand passing"35 between TNFR2 and TNFR1
might be expected to lower the concentration of TNF- needed for
TNFR1 signal transduction.34 Unfortunately, no mention was
made in any of these reports32 33 34 with
respect to the
effects of TNF- or lipopolysaccharide on cardiac
function. Finally, it should be recognized that our findings with
respect to the effects of stimulating TNFR1 in cardiac myocytes are
consistent with previous studies that show that the majority of
the pleiotropic biological activities of TNF-, including the
cytotoxic effects of this molecule, are signaled through
TNFR1.36 37
Despite the straightforward simplicity of the above findings with
respect to the TNF- mutants, these results must be interpreted
cautiously because the absolute specificity of binding of the human
TNF- mutants to feline TNF receptors was not directly confirmed in
the study. Finally, despite the similarities between feline and primate
myocytes in terms of their calcium metabolism and
mechanical and electrophysiological
properties, it should be recognized that results obtained in feline
myocytes may not be directly applicable to primate myocytes.
Conclusions
The elaboration of TNF- in destructive
pathophysiological contexts, such as acute
viral myocarditis,9 38 cardiac allograft
rejection,10 39 myocardial
infarction,40 41
myocardial reperfusion injury,42 and end-stage congestive
heart failure,11 43 suggests that TNF- may play
an
important role in modulating the left ventricular
dysfunction that supervenes in these conditions. Despite the potential
importance of TNF- in these cardiac disease states, very little is
known with respect to the basic mechanisms for the effects of TNF-
in the heart. The results of the present study appear to be
important for two reasons. First, the finding that cardiac myocytes
express receptors for TNF- provides a rational framework for
studying the signal transduction pathways that mediate the negative
inotropic effects of TNF-, as well as for designing effective
strategies to abrogate the negative inotropic effects of TNF-.
Second, this study provides a basis for future studies, in which we
will be able to determine whether TNF receptors are upregulated or
downregulated in cardiac disease states in which TNF- is believed to
play a deleterious
role5 6 7 8 9 10 11 42
as well as to determine
what might be the functional consequences of such TNF receptor
regulation.
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Acknowledgments |
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This work was supported in part by funds from the Veterans Administration and by an educational grant from Merck and Company. The authors gratefully acknowledge the secretarial assistance of Jana Grana and Adrienne Chee and the technical assistance of Dorellyn Lee-Jackson, Faye Savafi, and Shaista Khan. We would like to thank Dr Andrew Schafer and Dr Robert Roberts for their ongoing support and guidance. Finally, we would like to thank both reviewers for their thoughtful criticisms of the manuscript.
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Footnotes |
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The Guest Editor was William H. Barry, MD, University of Utah Medical Center (Salt Lake City).
Two separate but interrelated control studies were performed to
validate the use of the human TNF mutants in feline cells. In the
initial series of experiments, we determined that the binding of human
125I–TNF- was similar in human and feline
peripheral mononuclear cells. For these studies, human and
feline peripheral blood mononuclear leukocytes were
harvested using Ficoll gradient centrifugation
(Lymphocyte Separation Medium, Organon Teknika). Competition binding
assays were performed with recombinant human 125I–TNF-
as described in "Methods."28 Fig 5
shows two salient points with respect to these studies. First, there
was saturable binding of recombinant human 125I–TNF- to
both human and feline peripheral blood mononuclear cells.
Second, the binding affinities for 125I–TNF were very
similar for human
(Kd=2.7x10-10)
and feline
(Kd=3.4x10-10)
peripheral blood mononuclear cells. In the second series of
experiments, we examined the competitive binding of TNF mutants in
feline and human peripheral blood mononuclear cells. Fig 6,
which is a summary of the results of these studies,
demonstrates that the degree of competitive binding of TNFM2 to
peripheral blood mononuclear cells was greater than for
TNFM1, consistent with the fact that TNFR2 is the predominant
cell type in peripheral blood mononuclear
cells.23 Moreover, this figure shows that the degrees of
competitive binding for TNFM1 and TNFM2 were similar in the feline and
human cells. Taken together, the results show that binding of
recombinant human TNF- is similar in human and feline
peripheral blood mononuclear cells and that the binding of
the human TNF mutants is similar in human and feline
peripheral blood mononuclear cells. Thus, these studies
provide indirect data for the specificity of the binding of the human
TNF- mutants to feline TNFR1 and TNFR2.
Received August 3, 1994; revision received March 15, 1995; accepted March 26, 1995.
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