Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation.

Abstract

The functional capacity of the human monocyte receptor for the Fc portion of IgA (Fc alpha R) in mediating signal transduction was evaluated by cytokine release. F(ab')2 fragments of anti-Fc alpha R monoclonal antibodies (mAb) were used as specific probes to induce release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Multivalent cross-linking by a secondary anti-mouse antibody [F(ab')2 fragments] induced a significant release of TNF-alpha and IL-6 by human blood mononuclear cells, indicating requirements for Fc alpha R aggregation on the cell surface to transmit signals. Both cytokines were released exclusively by adherent cells, identifying monocytes as the responding cells within the mononuclear cell population. This cytokine release could not be due to contaminating endotoxins, because it was not abolished by polymyxin B, a lipopolysaccharide (LPS) inhibitor. Moreover, purified recombinant soluble Fc alpha R inhibited the anti-Fc alpha R mAb-mediated cytokine release from blood monocytes, demonstrating that TNF-alpha and IL-6 were released in a receptor-specific manner. Our data suggest that Fc alpha R, through its capacity to mediate secretion of IL-6, may play an important role in B-cell proliferation and immunoglobulin production. On the other hand, release of TNF-alpha following stimulation of Fc alpha R molecules directly implicates these receptors in amplification and regulation of the inflammatory process occurring during IgA-mediated host defence.

Full text

Page 1

Immunology 1995 86 1-5
Fca receptors mediate release of tumour necrosis factor-a and interleukin-6 by
human monocytes following receptor aggregation
C. PATRY, A. HERBELIN, A. LEHUEN, J.-F. BACH & R. C. MONTEIRO Institut National de la Santeet de la
Recherche Medicale, Unite 25, H6pital Necker, Paris, France
SUMMARY
The functional capacity of the human monocyte receptor for the Fc portion of IgA (FcaR) in
mediating signal transduction was evaluated by cytokine release. F(ab')2 fragments of anti-FcoaR
monoclonal antibodies (mAb) were used as specific probes to induce release of tumour necrosis
factor-a (TNF-at) and interleukin-6 (IL-6). Multivalent cross-linking by a secondary anti-mouse
antibody [F(ab')2 fragments] induced a significant release of TNF-ax and IL-6 by human blood
mononuclear cells, indicating requirements for FcaR aggregation on the cell surface to transmit
signals. Both cytokines were released exclusively by adherent cells, identifying monocytes as the
responding cells within the mononuclear cell population. This cytokine release could not be due to
contaminating endotoxins, because it was not abolished by polymyxin B, a lipopolysaccharide
(LPS) inhibitor. Moreover, purified recombinant soluble FcaR inhibited the anti-FcaR mAb-
mediated cytokine release from blood monocytes, demonstrating that TNF-at and IL-6 were
released in a receptor-specific manner. Our data suggest that FcaR, through its capacity to mediate
secretion of IL-6, may play an important role in B-cell proliferation and immunoglobulin
production. On the other hand, release ofTNF-ax following stimulation ofFcaR molecules directly
implicates these receptors in amplification and regulation of the inflammatory process occurring
during IgA-mediated host defence.
INTRODUCTION
Large numbers of cytokines are released during host injury
through triggering of monocytes by several soluble factors,
including products of the humoral immune responses. For
example, activation signals can be transmitted to cells through
a well-defined interaction between antigen-antibody com-
plexes and Fc receptors (FcR).1 It has been shown that cross-
linking of FcyR molecules by IgG2-4 or receptor-specific
monoclonal antibodies (mAb)5 results in release of several
cytokines, including interleukin-1
necrosis factor-a (TNF-x), which either directly mediate the
inflammatory process or amplify immune responses.
IgA Fc receptors (FcaR) have been described on mono-
cytes, neutrophils and eosinophils as heterogeneously glyco-
sylated proteins varying from 55 000 to 100 000 MW.6-8 These
receptors can bind monomeric and polymeric IgAl and IgA2
antibodies via their Fc regions.7 The sequence from a cDNA
encoding for FcaR identified
transmembrane protein belonging to the immunoglobulin and
(IL-1), IL-6 and tumour
this receptor as a type
I
Received 14 March 1995; revised 18 May 1995; accepted 23 May
1995.
Abbreviations: FcaR, receptor for Fc portion of IgA; sol-FcaR,
recombinant soluble FcaR.
Correspondence: Dr. R. C. Monteiro, INSERM U25, Necker
Hospital, 161, rue deSevres, 75743Paris, France.
(
1995 Blackwell Science Ltd
FcR families.9 Five mAb have been used to characterize the
expression and
designated as CD89.
The identification of FccxR has elucidated the link between
phagocytic cells and IgA antibodies, which can result in a
variety ofresponses, including superoxide generation, release of
inflammatory mediators, phagocytosis and killing of micro-
organisms.'2 Elevated levels of IL-1, IL-6 and TNF-cx were
detected in sera from patients with diseases associated with
increased polyclonal IgA, including IgA nephropathy, alco-
holic liver cirrhosis and acquired immunodeficiency syndrome
(AIDS),'3-16 suggesting that FcaR may be involved in this
process.
The present study addressed the functional properties of
FcoeR molecules by studying cytokine production after specific
receptor triggering on human monocytes, using F(ab')2 frag-
ments of anti-FcaR mAb' 1 and an inhibitor, the recombinant
soluble FcoxR (sol-FccxR),17 that specifically blocks the binding
site of anti-FcaR mAb.
structure of FcocR proteinsl0"',
recently
MATERIALS AND METHODS
Reagents
The mouse mAb used were A59, A62 and A77 (y1K), all specific
for FcaR." Control antibodies were irrelevant mouse IgG 1K
produced in our laboratory. F(ab')2 fragments of A59 and
1

Page 2

C. Patry et al.
A77 mAb and the IgGlK control were made by pepsin (Sigma
Chemical Co., St Louis, MO) digestion [enzyme to substrate
ratio (w/w) 1/50 in 0 1 M acetate buffer, pH 4 0, for 8 hr at 370],
and were affinity purified over rat anti-mouse K chain mAb
coupled to Sepharose 4B beads. Complete digestion and
F(ab')2 purity were established by sodium dodecyl sulphate-
polyacrylamide gel electrophoresis (SDS-PAGE). Goat anti-
mouse immunoglobulin antibodies were purchased from Southern
Biotechnology Associates (Birmingham, AL), extensively adsor-
bed against human paraproteins, pepsin digested to prepare
F(ab')2 fragments as described elsewhere,'8 and coupled to
CNBr-activated Sepharose 4B beads.
Preparation of Sol-FcoxR
Sol-FcaR had been produced previously by removing the
transmembrane and cytoplasmic coding regions from full-
length FcaR cDNA and ligating it into a mammalian expression
vector.17 Supernatants of COS-7 cells transfected with the sol-
FcaR plasmid(kindly provided by Dr C.
Immunex, Seattle, WA) were purified by using an anti-FcocR
(A59) mAb immunoaffinity column, as described elsewhere.'7
Purified sol-FcocR was stored at
50,g/ml. The irrelevant control preparation (sol-FcaR-) was
obtained by passing supernatants from COS-7 cells transfected
with plasmids containing cDNA in reverse orientation over the
A59 affinity column. The functional capacity of purified sol-
FcoaR was verified by dose-dependent inhibition of A59 anti-
FcaR mAb reactivity to phorbol myristate acetate (PMA)-
activated U937 cells, by flow cytometry using a FACScan (Becton
Dickinson, Mountain View, CA), as described previously.17
Maliszewski,
- 800
at a concentration of
Isolation ofhuman mononuclear cells and monocytes
Peripheral blood mononuclear cells (PBMC) were isolated
from heparinized blood ofhealthy donors by centrifugation over
Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) density gradi-
ents. The number ofmonocytes was evaluated by morphological
characteristics after May-Gruinwald-Giemsa staining, and the
PBMC were plated at a concentration of 105 monocytes/well in
flat-bottomed 96-well microtitre plates. In some experiments,
adherent cells were obtained by incubation of PBMC (106/ml)
for 2 hr at 37° in 96-well plates using RPMI-1640 supplemented
with 5% autologous serum. Non-adherent cells were obtained
after three cycles of plastic adherence in Petri dishes.
Cell stimulation
F(ab')2 fragments of A59 and A77 mAb and IgG 1k control
mAb were used either in soluble form or co-incubated with
F(ab')2 fragments of goat anti-mouse immunoglobulin anti-
bodies coupled to Sepharose 4B beads. In some experiments,
mAb were directly coupled to beads. Beads were first washed in
RPMI-1640 medium (Gibco, Grand Island, NY) containing
penicillin-streptomycin, 2mM
inactivated fetal calf serum (FCS). The stimulating material
was then preincubated with polymyxin B (20,g/ml) for
37°, except in experiments where cells were stimulated with
lipopolysaccharide (LPS; 5ng/ml, Escherichia coli 055:B5, L-
2880; Sigma). This concentration ofpolymyxin B fully inhibited
TNF-oc and IL-6 release induced by 1-5 ng/ml LPS. Cells (105
monocytes/well) were cultured for 18 h in 0-2ml RPMI- 1640
culture medium at 37° in a humidified atmosphere with 7% CO2
in the presence of the various stimuli. After incubation, culture
L-glutamine and
10%
heat-
1 hr at
supernatants were separated by centrifugation (Omin at 600g)
and then stored at - 70° until assay. For inhibition experiments,
the stimulating material was preincubated for 1 hr with sol-FcacR
or sol-FcaR- before addition to the cell cultures.
Assays ofcytokines
Enzyme-linked immunosorbent assays (ELISA; kindly pro-
vided by Dr D. De Groote, Medgenix Corp. Research and
Development Department,
Fleurus,
according to the manufacturer's instructions for determining
TNF-oa and IL-6 in culture supernatants. The detection limits
for TNF-oc and IL-6 were 10 pg/ml, and samples below the
detection limit were assumed to have values below 5 pg/ml.
Biological activities for TNF-a and IL-6 were determined with
the L929 tumour cell line cytotoxic assay and IL-6-dependent
cell line B9, respectively.'9' 20
Belgium) were used,
Statistical analysis
Each representative experiment is a typical result obtained with
cells from a single donor; it was verified that at least three
donors gave a similar pattern of results. Results are expressed
as mean + SEM and were compared using Student's paired t-
test.
RESULTS
Induction of TNF-cx and IL-6 release through triggering of FcacR
molecules
To examine the functional capacity of FcaR molecules in
transducing signals for secretion of IL-6 and TNF-a, crude
mononuclear cell populations from normal individuals were
cultured with
F(ab')2fragments
eliminate unrelated FcyR triggering via the mAb Fcy portion.
Preliminary dose-response experiments performed on PBMC
from two donors indicated that an optimal response was
obtained with between 2 and 10 jug/ml of F(ab')2 fragments of
anti-FcaR mAb coupled to beads (data not shown). Results
obtained from three different donors (Table 1) demonstrated
of anti-FcaR mAb
to
Table 1. FcaR-mediated release of cytokines by human mononuclear
cells
Donor
1
2
3
F(ab')2 beads*
TNF-zt
IL-6t
TNF-cx
IL-6
TNF-a
IL-6
IgG 1
A59
176
2306
18
148
1893
30
69
23
747
5121883
970
PBMC from three different donors were cultured for 20 hr in the
presence of Sepharose 4B beads coupled to either control F(ab')2
fragments of irrelevant IgGI or F(ab')2 fragments of A59 anti-FcaR
mAb. Culture supernatants were assayed by immunoassays specificfor
TNF-oc and IL-6. Significance was evaluated using Student's t-test: A59
F(ab')2 beads versus control IgGl F(ab')2 beads; P = 0 004 and
P = 0-033 for TNF-a and IL-6, respectively. Differences obtained for
control IgGI F(ab')2 beads and medium (110 + 35 and 22 ± 7pg/ml
for TNF-a and IL-6, respectively) were not significant.
*5pgof mAb/ml of packed beads.
t pg/ml.
© 1995 Blackwell Science Ltd, Immunology, 86, 1-5
2

Page 3

Fcax receptor-mediated cytokine production
that incubation of PBMC for 18 hr with 5yg/ml F(ab')2
fragments of A59 anti-FcaR mAb coupled to beads, in the
presence of 20 ,ug/ml polymyxin B, induced secretion of
both TNF-a (mean + SEM; 2027 ± 241 pg/ml) and
(743 ± 229 pg/ml) in all donors. The same donors exhibited
approximately 20-30-fold lower constitutive production of
TNF-a and IL-6 with control medium, and no significant
induction was observed with F(ab')2 fragments of irrelevant
IgG1-coupled to beads. Similar results were also obtained with
papain-digested Fab fragments coupled to beads of another
anti-FcaR mAb, A62 (data not shown). These results were
confirmed by biological assays for TNF-a and IL-6 (data not
shown).
IL-6
FcaLR-mediated release of cytokines requires multivalent
cross-linking
To determine whether cytokine release mediated by FcaxR was
dependent on receptor aggregation, the respective effects of
anti-FcaxR F(ab')2 fragments, either in soluble form alone or co-
incubated with F(ab')2 fragments of goat anti-mouse antibody-
coupled beads, were compared. As illustrated in Fig.
F(ab')2 fragments ofboth A59 and A77 mAb were ineffective in
inducing TNF-a release by PBMC, compared to those cross-
linked by the secondary anti-mouse antibody coupled to beads.
Cross-linking with A77 mAb induced a TNF-ax release threefold
higher than that obtained with A59 mAb (7402 versus 2468 pg/ml,
respectively).
1, soluble
Specificity of FccaR-induced cytokine release performed by
inhibitory assays using recombinant soluble FcoaR molecules
(sol-FcaxR)
To demonstrate the specificity of activation through FcaxR
molecules, we studied the inhibition of cytokine release by
8-
6-
' 4-
oJ
ELD
Cross-linked
mAb
Soluble mAb
Figure 1. TNF-a release after multivalent cross-linking of FcaR. PBMC
(adjusted to 105 monocytes/well) were incubated for 18 hr with soluble
F(ab')2 fragments of tested mAb (5 pg/ml) alone or cross-linked by
F(ab')2 fragments of goat anti-mouse immunoglobulin coupled to
Sepharose 4B beads (IOg/ml). Culture supernatants were assayed by
immunoassays specific for TNF-a. Open columns represent control
IgG1 F(ab')2 fragments, whereas hatched and black columns represent
the two anti-FcaR mAb F(ab')2 fragments, A59 and A77, respectively.
This is representative of three experiments performed with different
blood donors.
t 1995 Blackwell Science Ltd, Immunology, 86, 1-5
10-
E
-5
z
0
sol-FcaR-
sol-FcaR+
4
E
(0
_
+
+
_-++
Figure 2. Specificity ofanti-FcacR mAb-induced TNF-a and IL-6 release
determined by inhibitory assays using sol-FcaR. PBMC (105 mono-
cytes/well) were stimulated for 18 hr with A77 F(ab')2 fragments (5Pg/
ml), or control IgG
F(ab')2 fragments plus F(ab')2 fragments of goat
anti-mouse antibodies coupled to beads (10 ,ug/ml), in the presence or
absence of sol-FcaR (25
pg/ml), and with a control preparation
(sol-FcaR-) obtained from COS-7 transfected with plasmids contain-
ing reverse-orientation sol-FcaR cDNA. Culture supernatants were
tested for TNF-a and IL-6 by specific immunoassays. Similar results
were also obtained in three additional experiments.
co-incubation of the anti-FcaxR mAb with either sol-FcaR or
sol-FcaxR-, the control preparation. The latter was obtained
from supernatants of COS-7 cells transfected with plasmid
containing sol-FcaxR cDNA in the reverse orientation. Figure 2
shows that production of TNF-ac and IL-6 induced by anti-
FcaR mAb was completely abolished by addition of sol-FcaR
(25,g/ml; giving 83% and 87% inhibition ofTNF-a and IL-6,
respectively), whereas the control sol-FcaR- had no significant
effect.
FcaR-mediated cytokines are released by monocytes
As the FcaR recognized by these anti-FcaR mAb
exclusively expressed on cells of the myeloid lineage,'1 we
verified that monocytes were the only responding cells to FcaXR
cross-linking within the total mononuclear cell population.
PBMC were separated into two populations based on the
adherence properties of monocytes. As illustrated in Fig. 3,
monocytes appeared to be the main source of TNF-a and IL-6
in response to stimulation with F(ab')2 fragments of A77 anti-
FcaR mAb plus anti-mouse antibody coupled to beads. In
accordance with this, a significant TNF-a and IL-6 release was
observed after stimulation of adherent cells (3154 pg/ml and
1459 pg/ml, respectively), whereas non-adherent cells failed to
release significant amounts of these cytokines (191 pg/ml and
9 pg/ml,
respectively). Addition of non-adherent
adherent cells increased the release of both TNF-xt and IL-6
(5028 pg/ml and 3243 pg/ml, respectively),
lymphocytes may play an indirect role amplifying cytokine
release by monocytes. Cytokine levels were similar to those
obtained with the whole unseparated PBMC population
(5018 pg/ml and 2290 pg/ml, respectively). In an additional
experiment with
mediated TNF-a release by adherent cells was also inhibited
by addition of sol-FcaR, indicating further the specificity ofthe
FcaR response to the A77 antibody (610 pg/ml with sol-FcaR
were
cells
to
suggesting that
a different donor, A77 anti-FcaR mAb-
3

Page 4

C. Patry et al.
6
4
E
1-a|3
-
|.
2
Cs
LL
z
F-
A7
Control
A77
Control
A77
Figure 3. Anti-FcoR mAb-mediated TNF-a and IL-6 production is
restricted to monocytes. Adherent(0)and non-adherent cells (E) were
stimulated for 18 hr with A77 or IgGI control F(ab')2 fragments (5 jg/ml)
plus goat anti-mouse beads (10pg/ml).As controls, unseparated PBMC
(O-1) and mixed populations (M) were stimulated in the same conditions.
Culture supernatants were tested by immunoassays specific for TNF-a
and IL-6. Similar results were obtained in two additional experiments.
versus 1787 and 2192 pg/ml with
respectively).
or without sol-FcaR-,
DISCUSSION
In the present study, the functional capacity ofFcaR molecules
to mediate cytokine release was addressed by using F(ab')2
fragments of anti-FcaR mAb, and recombinant sol-FcaxR as
specific probes. Multivalent cross-linking of FcaR by three
anti-FcaR mAb induced a significant release of both TNF-a
and IL-6 by monocytes. A77 mAb triggered more FcaR
release of cytokines than the other two mAb, A59 and A62.
This suggests that different functional properties of FcoaR
epitopes are recognized by these anti-FcaxR mAb, as described
for other molecules such as Thy-1.21 This study demonstrates
a direct role of FcaR molecules in the mediation of cyto-
kine production. Stimulation of the FcacR resulted in TNF-ac
and IL-6 release by monocytes but not lymphocytes, as would
be expected, as FcaR are expressed selectively on myeloid
cells.7'9"'
Endotoxins, well-known monocyte activators, often con-
taminate biological materials and may contribute to triggering
the secretion ofcytokines such as TNF-a and IL-6.22 However,
several findings rule out the possibility of cytokine production
due to LPS contamination in our assays: (1) soluble anti-FcaR
mAb alone did not have a direct effect on monocytes, whereas
LPS at concentrations as low as 10-20 pg/ml (which were
undectectable in the Limulus assay) significantly stimulated IL-
6 release under the same culture conditions; (2) polymyxin B,
an LPS inhibitor, was added to all culture stimulations; and (3)
addition of recombinant sol-FcaR product, which specifically
blocks the binding site of anti-FcaR mAb, led to complete
inhibition of cytokine release.
Our findings expand and validate the observations of
other investigators, who have shown significant effects of
purified IgA on the release of inflammatory cytokines by
monocytes. In these studies, TNF-a release was observed after
stimulation with polymeric IgA'5 or IgA-immune complexes,23
but not with monomeric IgA. These observations
agreement with our results, indicating that FccxR-mediated
are in
release ofcytokines requires receptor aggregation to deliver cell
signals.
Aggregation of FcBR and FcyR molecules on different cell
types delivers transducting signals that result in production of
several cytokines.24 Our data on production of cytokines via
FcaR molecules indicate that these receptors may transduce
signals following aggregation, despite the absence of tyrosine
residues in the predicted cytoplasmic tail of the FcoeR.9 In
recent elegant studies, Pferfferkorn & Yeaman25 have shown
that FcaR molecules from a monocytic cell line (U937) are
associated with the FceRI-y2 subunits, indicating that the
FcaR-mediated signals described here may be transmitted via
the y chain tyrosine motifYXXL/I,26 as described for other Fc
receptors including FcERI, FcyRI and FcyRIII."'24 Interest-
ingly, in the latter study,25 only multivalent cross-linking of
FcoeR by anti-FcaR mAb plus anti-mouse antibodies resulted in
phosphorylation of the FcaR-y2 subunits. This is in agree-
ment with our data, that only multivalent cross-linking ofFcaR
induced by F(ab')2 fragments of anti-FccxR mAb plus F(ab')2
fragments of anti-mouse antibodies, but not F(ab')2 fragments
alone, mediated the release of cytokines.
The fact that all three anti-FcaR mAb, including A62,
induced cytokine release indicates that all previously described
heterogeneously glycosylated FcaR" may transduce signals
required for cytokine production. This is in agreement with the
observation that A62-reacted FcoaR molecules are also non-
covalently associated with FcERI-y2 subunits.25
The multifunctional cytokines TNF-c and IL-6 have been
described as central mediators of multiple inflammatory and
immune reactions.27'28 Release of TNF-a and IL-6 by trigger-
ing the FcaR reveals an additional effector function for
monocytes
in IgA-mediated inflammatory
TNF-a promotes an up-regulation of FccxR expression on
monocytes,29 it is likely that TNF-a release following FcaR
cross-linking may form a positive feedback loop where IgA-
immune complexes could stimulate TNF-ac production via
FcaR, and TNF-cx promote FcaR expression.
FcaR-mediated release of IL-6 may also indirectly enhance
IgA synthesis by B cells. This was first suggested by clinical
studies in patients with alcoholic liver cirrhosis, in which cross-
linking ofFccxR by IgA induced IL-6 release by monocytes, and
conversely anti-IL-6 mAb abrogated IgA production.'5 The
role of IL-6 in IgA production has been demonstrated recently
in mice with targeted disruption of the gene encoding IL-6.
These mice have a profound reduction in the number of IgA-
producing cells and have grossly deficient local antibody
responses on mucosal challenge.30 Interestingly, this defect
was corrected by IL-6 gene therapy, demonstrating a critica
role for IL-6 in vivo in the development of a mucosal IgA
antibody response.
As FcaR-binding
endogenous IgA in blood phagocytic cells from patients with
diseases associated with increased polyclonal IgA, including
IgA nephropathy, AIDS and alcoholiccirrhosis,31-33it islikely
that the continuous cross-linking of FcaR by IgA could be
responsible for the elevated levels of IL-1, IL-6 and TNF-a
observed in the serum of these patients.13-16Finally, the high
levels of TNF-a and IL-6 could play an important role in the
pathogenesis of such diseases by amplifying and regulating
inflammatory responses occurring during IgA-mediated host
defence.
© 1995 Blackwell Science Ltd, Immunology, 86, 1-5
responses. As
sites appeared
to be saturated by
4

Page 5

Fc.a receptor-mediated cytokine production
5
ACKNOWLEDGMENTS
We thank Dr C. Maliszewski for the generous gifts of sol-FcaR
plasmid, Dr D. De Groote for TNF-a and IL-6 ELISA kits, L.
Beaudoin for excellent technical assistance, and Dr M. Webb and Mrs
D. Broneer for critical reading ofthis manuscript. R.C. Monteiro was a
recipient of a grant from the Association pour la Recherche sur le
Cancer (no. 6490).
REFERENCES
1. RAVETCH J.V. & KINET J.P. (1991) Fc receptors. Annu Rev Immunol
9,457.
2. AREND W.P., JOSLIN F.G. & MAssoNi R.J. (1985) Effects ofimmune
complexes on production by human monocytes of interleukin 1 or
an interleukin 1 inhibitor. J Immunol 134, 3868.
3. DEBETS J.M., VAN DE WINKEL J.G., CEUPPENS J.L., DIETEREN I.E. &
BUURMAN W.A. (1990) Cross-linking of both FcyRI and FcyRII
induces secretion of tumor necrosis factor by human monocytes,
requiring high affinitty Fc-FcyR interactions. Funstional activation
of FcyRII by treatment with proteases or neuraminidase. J
Immunol 144, 1304.
4. KRUTMANN J., KIRNBAUER R., KOCK A. et al. (1990) Cross-linking
Fc receptors on monocytes triggers IL-6 production. Role in anti-
CD3-induced T cell activation. J Immunol 145, 1337.
5. LATOUR S., BONNEROT C., FRIDMAN W.H. & DAERON M. (1992)
Induction of tumor necrosis factor-alpha production by mast
cells via FcyR. Role of the FcyRIII gamma subunit. J Immunol
149, 2155.
6. ALBRECHTSEN M., YEAMAN G.R. & KERR M.A. (1988) Character-
ization of the IgA receptor from human polymorphonuclear
leucocytes. Immunology 64, 201.
7. MONTEIRO R.C., KUBAGAWA H. & COOPER M.D. (1990) Cellular
distribution, regulation, and biochemical nature ofan Fca receptor
in humans. J Exp Med 171, 597.
8. MONTEIRo R.C., HOSTOFFER R.W., COOPER M.D., BONNER J.R.,
GARTLAND G.L. & KUBAGAWA H. (1993) Definition of immuno-
globulin-A receptors on eosinophils and their enhanced expression
in allergic individuals. J Clin Invest 92, 1681.
9. MALISZEWSKI C. R., MARCH C.J., SCHOENBORN M.A., GIMPEL S. &
SHEN L. (1990) Expression cloning ofa human Fc receptor for IgA.
J Exp Med 172, 1665.
10. SHEN L., LASSER R. & FANGER M.W. (1989) My43, a monoclonal
antibody that reacts with human myeloid cells inhibits monocyte
IgA binding and triggers function. J Immunol 143, 4117.
11. MONTEIRo R.C., COOPER M.D. & KUBAGAWA H. (1992) Molecular
heterogeneity of Fca receptors detected by receptor-specific
monoclonal antibodies. J Immunol 148, 1764.
12. SHEN L. (1992) Receptors for IgA on phagocytic cells. Immunol Res
11, 273.
13. DECAESTECKER M.P., BoTTOMLEY M., TELFER B.A., HUTCHINSON
IV., VOSE B.M. & BALLARDIE F. W. (1993) Detection ofabnormal
peripheral blood mononuclear cell cytokine networks in human
IgA nephropathy. Kidney Int 44, 1298.
14. KHORuTus A., STAHNKE L., MCCLAIN C.J., LOGAN G. & ALLEN JI.
(1991) Circulating tumor necrosis factor, interleukin-1 and inter-
leukin-6 concentrations in chronic alcoholic patients. Hepatology
13, 267.
15. DEVIERE J., CONTENT J., DENYS C. et al. (1992) Immunoglobulin A
and interleukin 6 form a positive secretory feedback loop: a study
of normal subjects and alcoholic cirrhotics. Gastroenterology
103, 1296.
16. LAHDEVIRTA
Elevated levels of circulating cachectin/tumor necrosis factor in
patients with acquired immunodeficiency syndrome. Am J Med
85, 289.
17. MALISZEWSKI C.R., VANDENBOS T., SHEN L. et al. (1993) Recombi-
nant soluble IgA Fc receptor-generation, biochemical character-
ization, and functional analysis of the recombinant protein. J
Leukoc Biol 53, 223.
18. CHEVAILLER A., MONTEIRo R.C., KUBAGAWA H. & COOPER M.D.
(1989) Immunofluorescence analysis of IgA binding by human
mononuclear cells in blood and lymphoid tissue. J Immunol
142, 2244.
19. RUFF M.R. & GIFFORD G.E. (1981) Tumor necrosis factor. In:
Lymphokines, 2 (ed. E. Pick), p. 235. Academic Press, New York.
20. HERBELIN A., URENA P., NGUYEN A.T., ZINGRAFF J. & DESCAMPS-
LATSCHA B. (1991) Elevated circulating levels of interleukin-6 in
patients with chronic renal failure. Kidney Int 39, 954.
21. PONT S., REGNIER-VIGOUROUX A., NAQUET P. et al. (1985) Analysis
of the Thy-1 pathway cell hybridoma activation using 17 rat
monoclonal antibodies reactive with distinct Thy- 1 epitopes. Eur J
Immunol 15, 1222.
22. CHEN A.R., MCKINNON K.P. & KOREN H.S. (1985) Lipopolysac-
charide (LPS) stimulates fresh human monocytes to lyse actino-
mycin D-treated WEHI-164 target cells via increased secretion of
monokine similar to tumor necrosis factor. J Immunol 135, 3978.
23. LEVY POLAT G., LAUFER J., FABIAN I. & PASSWELL J.H. (1993)
Cross-linking ofmonocyte plasma membrane Fca, Fcy or mannose
receptors induces TNF production. Immunology 80, 287.
24. BEAVEN M.A. & METZGER H. (1993) Signal transduction by Fc
receptors - the FceRI case. Immunol Today 14, 222.
25. PFERFFERKORN L.C. & YEAMAN G.R. (1994) Association ofIgA-Fc
receptors (FcaR) with FceRI-y2 subunits in U937 cells. JImmunol
135, 3228.
26. RETH M. (1989) Antigen receptor tail clue. Nature 338, 383.
27. BEUTLER B. & CERAMI A. (1989) The biology of cachectin/TNF-a
primary mediator of host response. Annu Rev Immunol 7, 625.
28. VAN SNICK J. (1990) Interleukin-6: an overview. Annu Rev Immunol
8, 253.
29. SHEN L., COLLINS J.E., SCHOENBORN M.A. & MALISZEWSKI C.R.
(1994) Lipopolysaccharide and cytokine augmentation of human
monocyte IgA receptor expression and function. J Immunol
152, 4080.
30. RAMSAY A.J., HUSBAND A.J., RAMsHAw I.A. et al. (1994) The role of
interleukin-6 in mucosal IgA antibody responses in vivo. Science
264, 561.
31. MONTEIRO R.C., GROSSETETE B., NGUYEN A.T., JUNGERS P. &
LEHUEN A. (1995) Dysfunctions of Fca receptors by blood
phagocytic cells in IgA nephropathy. Contrib Nephrol 111, 116.
32. GROSSETErE B., VIARD J.P., LEHUEN A., BACH J.F. & MONTEIRO
R.C. (1995) Impaired Fca receptor expression is linked to increased
immunoglobulin A levels and disease progression in HIV-1-
infected patients. AIDS 9, 229.
33. SILVAIN C., PATRY C., LAUNAY P., LEHUEN A. & MONTEIRO R.C.
(1995) Altered expression of monocyte IgA Fc receptors
associated with defective endocytosis in patients with alcoholic
cirrhosis: potential role for IFN-y. J Immunol 155, 1606.
J., MAURY C.P., TEPPOAM J. & REPO H. (1988)
is
© 1995 Blackwell Science Ltd, Immunology, 86, 1-5