Immunohistochemical Localization of the Interleukin-1 System in the by xiaohuicaicai


									BIOLOGY OF REPRODUCTION 50, 449-457 (1994)

      Immunohistochemical Localization of the Interleukin-1 System in the Mouse Ovary
                   during Follicular Growth, Ovulation, and Luteinization1

   Department of Gynecology and Obstetrics, Stanford University Medical Center, Stanford, California94305

                 The distribution of immunoreactive interleukin-l receptor type I (IL-IR tI), IL-la, and IL-IP, and of macrophages, was in-
             vestigated immunohistochemically in the mouse ovary during follicular growth, ovulation, and luteinization. For this purpose, an
             indirect immunofluorescence technique, using specific monoclonal antibodies against mouse IL-1R tI, mouse IL-la, IL-l0, and
             macrophage antigens (CDllb/CD18) was used with sections of paraffin-embedded ovaries from eCG and eCG/hCG-treated 12-
             wk-old B6C3F-1 female mice. During follicular development, IL-la, IL-1p, and IL-IR tI staining were confined to the theca-
             interstitial layer of growing follicles with one remarkable exception. Intense IL-1R tI staining was present in the cytoplasm and
             plasma membrane of the murine oocyte. During ovulation, IL-la and IL-IPi were still confined to the theca layer, but faint IL-1R
             tI staining was initiated in cumulus cells and in granulosa cells just before follicle rupture. Immediately after follicle rupture,
             granulosa cells stained positive for IL-IR tl, IL-la, and IL-1l. During luteinization, granulosa-luteal cells of the corpus luteum
             demonstrated strong IL-1R tI, IL-la, and IL-ll staining. Macrophages were detected in the theca layer and stroma, but never
             within the follicle before ovulation. Immediately after ovulation, there was a rapid entry of macrophages into the follicle, and
             macrophages were also present inside the corpus luteum. Our morphological results support a possible autocrine-paracrine role
             of the mouse ovarian IL-i system in ovulation and luteinization.

                               INTRODUCTION                                                    losa cells [14]. However, others have shown that IL-la in-
    Paracrine cytokines produced by ovarian and lymphohe-                                      hibits LH-induced luteinization and progesterone produc-
matopoietic cells are increasingly implicated in the cyclic                                    tion of porcine granulosa cells [15, 16] and rat granulosa
events of ovarian physiology. Interleukin-1 (IL-1), a family                                   cells [17]. Resident ovarian macrophages have been im-
of polypeptides comprising IL-la, IL-13, and an inhibitor,                                     munohistochemically localized in the mouse ovary and
 interleukin-1 receptor antagonist (IL-lra) [1], is a major can-                               constitute a substantial cellular component of the intersti-
didate for this cooperative action. Two IL-1 receptors have                                    tial compartment [18]. IL-1 is an established immune me-
been identified and characterized: IL-1R type I (IL-1R tI [2])                                 diator produced by resident macrophages, and these cells
and IL-1R type II (IL-1R tII [3]). The type I receptor is found                                of the white blood cell series have been suggested as the
on most cells and appears to be important for transducing                                      main source of this cytokine in the ovary [19]. However,
the action of IL-1. The type II receptor is found primarily                                    because macrophage-depleted human granulosa-luteal cells
on B lymphocytes, neutrophils, and monocytes; its function                                     contain messenger RNAs for IL-la and IL-l1 [9], the intra-
                                                                                               ovarian source of these cytokines remains unclear. Inter-
is unclear. IL-1R tI recognizes both ligands, IL-la and IL-1{3,
                                                                                               estingly, the large body of literature implicating the IL-1 sys-
triggering similar responses in target cells [4]. IL-lra binds
                                                                                               tem in ovarian function contrasts with the absence of
to IL-1R tI and appears to prevent signal transduction by
                                                                                               morphological data concerning the localization of the IL-1
blocking the binding of IL-1 [5].
                                                                                               system in the cellular components of the ovary.
    In humans, preovulatory follicular fluid contains im-
                                                                                                  The present study was undertaken to examine the cel-
munoreactive IL-1 [6-8], and the presence of a complete
                                                                                               lular localization of IL-1R tI, IL-la, IL-13, and macrophages
intraovarian IL-1 system has been demonstrated [9]. In the
                                                                                               in the mouse ovary during follicular growth, ovulation, and
in vitro perfused rat ovary [10] and rabbit ovary [11], an
ovulatory effect of IL-1 has been documented. IL-1 has also
been implicated in the luteinization process, although this
is controversial. Some researchers have reported a positive                                                    MATERIAL AND METHODS
regulation of IL-1 on progesterone production and release                                      Animals and Animal Treatment
from human granulosa-luteal cells [12, 13] and rat granu-
                                                                                                  Twelve-week-old B6C3F-1 female mice were obtained
                                                                                               from Charles River Breeding Laboratories, Inc (Wilmington,
    Accepted September 28, 1993.
     Received August 11, 1993.
                                                                                               MA) and maintained at 22-240C on a 12L:12D cycle. Ani-
     'C.S. is a Postdoctoral Fellow supported by Subprograma General Extranjero grant          mals were monitored by daily vaginal smears. At proestrus,
from the Spanish Government, MEC, Madrid, Spain; on leave from the Department                  mice received i.p. injections of 5 IU eCG. Approximately 48
of Pediatrics, Obstetrics and Gynecology, Valencia University School of Medicine,
Valencia, Spain.
                                                                                               h after eCG, mice received i.p. injections of 5 IU hCG. Six
    2Correspondence: Carlos Sim6n, Instituto Valenciano de Infertilidad, Guardia Civil         animals from each stage were killed by cervical dislocation
23, 46020 Valencia, Spain.                                                                     at 24, 12, and 2 h before hCG and at 2, 4, 6, 12, 14, 16, and

450                                                                     SIMON ET AL.

TABLE 1. Summary of the immunohistochemical experiments
identifying IL-1R tl, IL-1, IL-1a, and macrophages in the mouse ovary
                                                                                 at 37°C; Sigma), and FITC-conjugated anti-hamster IgG mouse
during follicular development.                                                   adsorbed for 60 min (100 jig/ml at 37°C; Boehringer-
                                                                                 Mannheim). Slides were rinsed twice with PBS-T, mounted
                                  Ovarian follicle
                                                                                 with Vectashield mounting media (Vector Labs., Burlin-
                    Oocyte            cells          Theca layer     Stroma
                                                                                 game, CA), and photographed by use of an Olympus 35
IL-1R tl          +++/+++a              0/0             +/++         +/++
                                                                                 mm camera and an Olympus BH2 microscope fitted with
IL-1,8               0/0                0/0              +/+         ++/++       a BH-RFL-W reflected light fluorescence attachment. Rela-
IL-la                0/0                0/0              +/+          +/++       tive intensity of the immunostaining was evaluated by two
CD-llb/CD18          0/0                0/0              0/+         +/++
                                                                                 of the authors in a double-blinded manner as absent (0),
aDesignations of + (weakly positive) to +++ (intensely positive) indicate        weakly positive (+), moderate (++), or intense (+++)
 the relative intensities of the signals averaged for the specimens during
 follicular development; variability between readers is indicated with a slash   for at least three different specimens from each time point.
                                                                                 IL-1 System in the Mouse Ovary during FollicularGrowth
24 h after hCG administration. Ovaries and oviducts were                             IL-1R tI was localized in the oocyte and theca cells dur-
immediately removed for fixation in 10% formalin in PBS.                         ing follicular development before hCG administration (Fig.
                                                                                 1, Table 1). In the oocyte, cytoplasm and plasma membrane
Tissue Processing                                                                stained strongly, but the germinal vesicle in the immature
   Fixed tissue was embedded in paraffin, sectioned, and                         oocytes remained unstained (Fig. 1, A and B). IL-1R tI was
mounted on coated glass slides. Ten serial sections (6 ,m)                       not detected in either granulosa cells or cumulus cells in
from each sample were then prepared for immunohisto-                             healthy follicles (Fig. 1, A and B). Only in those follicles
chemistry, and the first and last section were stained with                      that appeared morphologically abnormal could an increase
hematoxylin-eosin (H&E) and viewed with an Olympus 35-                           of IL-1R tI be observed in granulosa and theca cells, ac-
mm camera and an Olympus BH2 microscope.                                         companied by a decreased staining in the oocyte (Fig. 1C).
                                                                                     During follicular development, localization of IL-la and
Immunohistochemical Staining                                                     IL-1P was not obvious within the follicle; only some cells
                                                                                 of the theca layer and stroma stained positively for both
    The immunostaining procedure was performed on mouse
                                                                                 cytokines (Fig. 1, D, E, and F). Macrophages were not pres-
ovary paraffin-embedded sections by an indirect immuno-
                                                                                 ent within the ovarian follicle before ovulation, isolated
fluorescence technique. Sections were deparaffinized in xy-                      macrophages could be seen only in the theca layer, and
lene and rapidly rehydrated through graded alcohols. Ex-
                                                                                 these cells were a major cellular component of the inter-
cess liquid was removed, and sections were washed in PBS
                                                                                 stitial tissue between developing follicles (Fig. 1G).
(pH 7.4) with 0.05% Tween-20 (PBS-T; Sigma Chemical Co.,
St. Louis, MO). To reduce the nonspecific binding, normal                        IL-1 System in the Mouse Ovary during Ovulation
goat serum (1% in PBS) was applied to slides for 30 min                             Immediately before follicle rupture (10-12 h after hCG;
at 37 0C. Sections were washed with PBS-T twice, and then                        Fig..2, Table 2), faint IL-1R tI staining could be observed in
incubated with the primary antibodies: monoclonal rat anti-
mouse IL-1R tI antibody, monoclonal hamster anti-mouse
IL-l1 antibody, monoclonal hamster anti-mouse IL-la an-                               FIG. 1. Immunohistochemical localization of IL-1R tl, IL-1, IL-la, and
tibody (all from Genzyme Corp., Cambridge, MA) at 50 jIg/                        macrophages in the mouse ovary during follicular growth. A) Preantral fol-
ml, 66.7 jig/ml, and 20 g/ml respectively, or rat mono-                          licle with two oocytes. IL-1R tl is strongly localized in the cytoplasm and
                                                                                 plasma membrane of the oocyte, but the germinal vesicle remains un-
clonal antibody to the mouse and human Mac-i antigen                             stained. IL-1R tl staining can also be seen in the theca layer and corpora
CDllb/CD18 (Anti-Mac-i, Boehringer-Mannheim, Indian-                             lutea surrounding this follicle. B) Antral follicle. IL-1R tl staining is present
                                                                                 in the same locations as in preantral follicles: cytoplasm and plasma mem-
apolis, IN) at 50 ILg/ml for 90 min at 37 0C on consecutive                      brane of the oocyte and theca layer. C) Morphologically. abnormal follicle
sections. Monoclonal hamster anti-mouse IL-lot does not                          (atretic follicle). Notice that the pattern for IL-1 Rtl is different. In the oocyte,
cross-react with human IL-lao or IL-13, or with mouse IL-                        there is obviously less staining in the cytoplasm, and staining is absent in
                                                                                 the plasma membrane. In the granulosa cells, IL-R tl is present in the plasma
11i, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, colony-stimulating factor,              membrane; this is never true of healthy follicles during follicular growth.
tumor necrosis factor-a (TNF-oa), or interferon-'y (IFN-y).                      In the theca layer, staining for IL-1R tl is increased. D) IL-I1 localization in
Hamster anti-mouse IL-1P does not recognize human IL-laot                        a preantral follicle. E) IL-[ localization in preantral and antral follicles. F)
                                                                                 IL-la staining in an antral follicle. In all cases (D-F), IL-1, and IL-la were
or IL-1p3, and no detectable cross-reactivity was observed                       not present within the follicle; only some cells of the theca layer and stroma
with mouse IL-loa, TNF-a, or IFN-y. Control incubations in-                      stained positive for both cytokines. G) Immunohistochemical detection of
cluded deletion of the primary antibody. After being rinsed                       mouse macrophages (CDllb/CD18) during follicular development. Isolated
                                                                                  macrophages can be seen in the theca layer, and these cells are a major
with PBS-T, sections were incubated with specific second-                        cellular component of the interstitial tissue between developing follicles. H)
ary antibodies: fluorescein isothiocyanate (FITC)-conju-                          Negative control by deletion of the primary antibody. Bar = 10 im in all
gated anti-rat IgG mouse adsorbed for 60 min (16 g/ml                             plates.
452   SIMON ET AL.
                                                     INTERLEUKIN-1 SYSTEM IN THE MOUSE OVARY   453

TABLE 2. Summary of the immunohistochemical experiments
identifying IL-1R tl, IL-13, IL-la, and macrophages in the mouse ovary
during ovulation immediately before follicle rupture.
                                 Ovarian follicle
                   Oocyte     Cumulus Granulosa Theca layer            Stroma
IL-1R t          ++/+++a        +/++         +/0         ++/++        ++/+++
IL-1p              0/0           0/0         0/0          +/++        ++/+++
IL-la                0/0         0/0         0/0          +/++          +/++
CD-llb/CD18          0/0         0/0         0/0          +/++          +/++
'Designations of + (weakly positive) to +++ (intensely positive) indicate
 the relative intensities of the signals averaged for the specimens obtained
 10-12 h after hCG administration; variability between readers is indicated
 with a slash mark.

the plasma membrane of cumulus cells surrounding the
preovulatory oocyte and in granulosa cells (Fig. 2, A and
   Immunoreactive IL-13 (Fig. 2C) and IL-la (Fig. 2D) were
not localized in granulosa cells or cumulus cells. Only some
cells of the theca layer stained positively for both cytokines,
and staining did not increase prior to ovulation. Macro-
phages were not present within the ovarian follicle before
ovulation, but were a major cellular component of the in-
terstitial tissue (Fig. 2E).
   Immediately after follicle rupture (14-16 h after hCG
administration; Fig. 3, Table 3), IL-1R tI staining in granu-
losa cells was increased (Fig. 3A), and these cells were sud-
denly able to produce IL-la and IL-l1 (Fig. 3B) An entry
of CDllb/CD18 antigen-positive blood cells representing
macrophages/monocytes was also observed within the
ovulated follicle (Fig. 3C). These cells of monocyte/mac-
rophage lineage also exhibited intense staining for IL-1R tI
(Fig. 3A), IL-la, and IL-1P (Fig. 3B).
   In the oviduct 24 h after hCG administration (Fig. 4),
isolated cumulus cells surrounding the unfertilized oocyte
exhibited increased staining for IL-1R tI in the plasma mem-
brane (Fig. 4A); the unfertilized oocyte and its polar body
within the oviduct also retained intense IL-1R tI staining in
the cytoplasm (Fig. 4A). IL-la and IL-13 staining was initi-
ated in both the oocyte and a few isolated cumulus cells
(Fig. 4B). Macrophages were not detected in the oviduct at
this time.

     FIG. 3. Immunohistochemical localization of IL-1R tl, IL-13, and mac-
 rophages in the mouse ovary immediately after follicle rupture, 14 h after
 hCG administration. A) IL-R tl staining. Notice that IL-1 Rtl staining in gran-
 ulosa cells is increased compared with the IL-1R tl staining present in cu-
 mulus cells. Entry of cells exhibiting intense staining for IL-R tl is also
observed. B) IL-p staining (adjacent section to A). Granulosa cells abruptly
acquire the capability to produce IL-18 (compare with IL-p staining present
in the theca layer). The cells that recently entered the follicle exhibit intense
staining for IL-1. C) CD11b/CD18 antigen staining in the adjacent section
of B. Notice that a large group of new cells that invaded the follicle im-
mediately after follicular rupture are immunohistochemically characterized
as mouse macrophages. Bar = 10 m in all plates.
                  TABLE 3. Summary of the immunohistochemical experiments identifying IL-1R tl, IL-lp, IL-la, and macrophages
                  in the mouse ovary during ovulation immediately after follicle rupture.

                                                                          Ovarian follicle
                                             Oocvte               Cumulus              Granulosa            Theca laver             Stroma

                   IL-IR t l               +++/+++a               ++/++                 ++/+++                ++/+++               ++/+++
                   IL-1p                       o/+                  o/+                +++/+++               +++/+++               ++/+++
                   IL-la                       o/+                  o/+                +++/+++               +++/+++               ++/+++
                   CD-I lb/CD18                                  +++/+++                                       +/++                ++/+++
                  "Designations of + (weakly positive) to +++ (intensely positive) indicate the relative intensities of the signals averaged
                   for the specimens obtained 12-14 h after hCG administration; variability between readers is indicated with a slash

IL-1 System in the Mouse Ovary during Luteinization                               growing follicles (Figs. 1 and 2). These observations are in
   After hCG administration, as luteinization progressed (Fig.                    agreement with the described presence of IL-IP mRNA in
5, Table 4), increased staining for IL-lR tI was seen in the                      the theca-interstitial layer in the rat ovary [20] and the dem-
cytoplasm of granulosa-luteal cells (Fig. 5A), and the mature                     onstrated effect of IL-la on theca cells in preovulatory ham-
corpus luteum exhibited even stronger IL-1R tI staining (Fig.                     ster follicles [21]. In addition, similar morphological results
5B). Cytoplasmic IL-la and IL-IP staining was present in                          regarding the absence of IL-la and IL-1P staining in gran-
granulosa-luteal cells, with increased staining in the mature                     ulosa cells from human preovulatory follicles have been
corpus luteum (Fig. 5, C and D). Some macrophages could                           reported by our laboratory [22].
also be detected within the corpus luteum (Fig. 5F). Al-
though these cells also produced IL-la and IL-1P, macro-
                                                                                      FIG. 5. lmmunohistochemical localization of IL-1R tl. IL-la, IL-1P, and
phages were a relatively minor source of both cytokines                           rnacrophages in the mouse ovary during luteinization. A) IL-R t l staining in
and IL-1R tI in the corpus luteum compared with luteal cells                      a developing corpus luteum (20 h after hCG administration). Granulosa-
(Fig. 5, E and F).                                                                luteal cells exhibit progressively increased IL-1R tl staining; but during early
                                                                                  luteinization, IL-1R tl staining is stronger in macrophages (arrow). B) IL-R
                                                                                  tl staining in a mature corpus luteum (2 days after hCG administration).
                             DISCUSSION                                           There is an increase IL-R t l staining in the cytoplasm of granulosa-luteal
   The immunohistochemical observations in the present                            cells (compared with A, common reference oocyte staining). C) IL-la stain-
                                                                                  ing in a developing corpus luteum (adjacent section to A). Granulosa-Meal
study demonstrate for the first time a simultaneous locali-                       cells show progressively increasing IL-la staining. D) IL-p staining in a ma-
zation of IL-lR tI, IL-la, and IL-1P in different cell types of                   ture corpus luteum (2 days after hCG administration). Cytoplasmic IL-p
the mouse ovary, with differential expression during follic-                      staining is present in granulosa-luteal cells, showing a pattern similar to
                                                                                  that of IL-IR tl. E) IL-R t l staining in granulosa-luteal cells 2 days after hCG
ular growth, ovulation, and luteinization.
                                                                                  administration, detail of B (arrow as a reference). F) Detail of macrophages
   During follicular development, IL-la, IL-1P and IL-1R tI                       staining in a mature corpus luteum 2 days after hCG. Bar = 10 Fm in all
staining were confined to the theca-interstitial layer of                         plates.

     FIG. 4. lmmunohistochemical localization of IL-1R tl and IL-1p in the unfertilized oocyte within the oviduct 24 h after hCG administration. A) IL-lR tl
staining in the mouse oviduct. The unfertilized oocyte retains IL-1R t l staining in the cytoplasm; notice that the polar body also stains positively for IL-IR
tl. An obvious plasma membrane staining for IL-1R tl in cumulus cells is also observed. B) IL-lp staining in the mouse oviduct section adjacent to A. IL-
1p staining has started initiated in the oocyte and a few isolated cumulus cells. Bar = 10 pm in all plates.
456                                                                   SIMON ET AL.

TABLE 4. Summary of the immunohistochemical experiments                            After ovulation, granulosa-luteal cells of the developing
identifying IL-1R tl, IL-1, IL-la, and macrophages in the mouse ovary
during luteinization.                                                          corpus luteum exhibited progressively increased IL-1R tI
                                                                               staining, and abruptly acquired IL-loa and IL-13 staining (Figs.
                                Corpus luteum
                                                                               3 and 5). IL-1 bioactivity in human serum reaches maximal
                     Developing                 Mature            Stroma
                                                                               levels after ovulation [30], which is consistent with our ob-
                                        +++/+++                  ++/+++
IL-1R tl+++a                                                                   servation that IL-1 production and action resided in the cor-
IL-1                  ++/+++            +++/+++                  ++/+++
IL-la                 ++/+++            +++/+++                  ++/+++        pus luteum. However, whether IL-1 modulates progester-
CD-llb/CD18     (grouped) +++/+++ (scattered)+++/+++             ++/+++        one production [12-17] or progesterone modulates IL-1
aDesignations of + (weakly positive) to +++ (intensely positive) indicate      production by granulosa-luteal cells seems controversial. It
 the relative intensities of the signals averaged for the specimens obtained   is likely that both situations occur and that the IL-1 system
 20-48 h after hCG administration. Distinction of developing and mature
 corpora lutea are based on histologic criteria. Variability between readers
                                                                               is implicated in the corpus luteum formation and function.
 is indicated with a slash mark.                                               The present work provides morphological support for this
                                                                               hypothesis. Furthermore, we demonstrated that hemato-
                                                                               poietic cells are not the predominant source of IL-1 in the
                                                                               corpus luteum. After ovulation, granulosa-luteal cells pro-
    Of particular interest is the fact that IL-1R tI at the pro-               gressively acquire the capacity to produce and bind IL-1 in
tein level was strongly expressed in the murine oocyte in-                      response to as yet unknown factors. Therefore, this cyto-
dependently of developmental follicular stage. Further-                        kine may act as a paracrine-autocrine mediator in the for-
more, this expression continued in oocytes found in the                         mation and function of the corpus luteum.
oviduct. Immunoreactive IL-iR tI detected in the oocyte could                       Interestingly, before ovulation the presence of mono-
be due to sequestration instead of production; however,                         cyte-macrophages was detected in the theca layer and stroma,
this is very unlikely since our finding is corroborated by                      but never within the follicle itself (Figs. 1 and 2). Imme-
the previously described presence of IL-1R tI mRNA within                       diately after ovulation, macrophages that possessed IL-1R tI
the murine oocyte by in situ hybridization [23]. The iden-                      and both ligands IL-la and IL-113 migrated into the ovulated
tification at the protein level of receptors in mammalian                       follicle (Fig. 3). Later on, macrophages were also detected
oocytes is certainly rare. As yet, only epidermal growth fac-                   within the corpus luteum (Fig. 5F). These results are in
tor receptor protein has been localized in human oocytes                        agreement with previous studies demonstrating the pres-
[24]. Insulin-like growth factor-I receptor mRNA has been                       ence of macrophages in the mouse ovary [18], rat ovary
identified in the human [25] and murine oocyte [26], and                        [31], and human ovary [32]. Our morphological observa-
the expression of the estradiol receptor gene has been                          tions of an intimate relationship of macrophages to luteal
 identified in the mouse oocyte by use of the reverse tran-                     cells support the demonstrated capability of macrophages
scriptase-polymerase chain reaction technique [27]. But none                    to stimulate progesterone production in the murine corpus
of these receptors has been identified as an immunoreac-                        luteum [33,34] and human granulosa-luteal cells [35]. To-
 tive protein in mammalian oocytes. Therefore, the remark-                      gether, this evidence invokes a cooperative role of mono-
 ably high levels of IL-1R tI protein in the oocyte may have                    cyte-macrophages in luteal tissue function.
 a previously unsuspected important physiological role(s) in                         In summary, our morphological study shows that the
 oocyte maturation. This hypothesis is reinforced by the fact                    mouse ovary is a site for IL-la and IL-13 production and
 that only morphologically abnormal oocytes had decreased                        action through its receptor, IL-1R tI. During follicular de-
 IL-1R tI staining (Fig. 1C). This observation may be most                       velopment, both ligands and receptor were confined to the
 intriguing, considering that human preovulatory follicular                      theca-interstitial layer of growing follicles. In addition, a
 fluid contains immunoreactive IL-1 [6-8], but according to                      dramatic increase of IL-1R tI, IL-la, and IL-i13 staining was
 our data, murine granulosa cells do not contain or produce                      observed in granulosa cells immediately before and after
 IL-1 prior to ovulation. Other sources of IL-1 known at this                    ovulation, and in the corpus luteum, supporting a possible
 time are thecal macrophages and peripheral monocytes. Our                       autocrine-paracrine role for the mouse ovarian IL-1 system
 group has demonstrated that estradiol and progesterone                          in both ovulation and luteinization.
 modulate human monocyte IL-1 activity [28] and IL-l1 mRNA
  levels [29]. This loop provides an IL-1 feedback control by
  steroids according to the differential functional status of                                                    REFERENCES
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