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From the Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia.
Correspondence to Dr. Peter G. Tipping, Monash University, Department of Medicine, Monash Medical Center, 246 Clayton Road, Clayton, 3168, Victoria, Australia. Phone: 61 3 9594 5547; Fax: 61 3 9594 4279; E-mail: peter.tipping{at}med.monash.edu.au
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-)
(4,7)
and interleukin-12 (IL-12) (8)
or by administration of Th2 cytokines IL-4 and IL-10
(9) attenuates crescentic GN.
Augmentation of Th1 responses by administration of IL-12
(8) or genetic absence of IL-4
(10) or IL-10
(11) exacerbates crescentic
GN.
IL-12 is a heterodimeric cytokine composed of two covalently linked
subunits, p35 and p40, encoded by separate genes
(12). Macrophages and
monocytes produce IL-12 as an early response to antigenic stimuli
(13). Antigen-presenting cells
produce IL-12 after engagement with activated T cells and co-stimulation via
CD40 ligand (14). IL-12 primes
CD4+ T cells for high IFN- production
(14,15)
and polarizes uncommitted T cells toward a Th1 profile. The role of IL-12 in
immune responses in vivo has been referred to as a "functional
bridge" between the early noncognate innate resistance and subsequent
antigen-specific adaptive immunity
(13,16,17).
IL-12 has been demonstrated in crescentic glomeruli of mice that are
susceptible to autoimmune anti—glomerular basement membrane
(anti-GBM)-induced GN but was not detectable in strains that are resistant to
the development of crescentic glomerular lesions
(6). In the autoimmune GN
associated with the "lupus like" syndrome of
MRL/Fas1pr mice, intrarenal IL-12 expression by
infiltrating mononuclear cells and tubular epithelial cells was demonstrated
in association with increased IFN- mRNA
(18). In vitro, renal
tubular epithelial cells produce IL-12 mRNA and low levels of IL-12 protein
(18), and mesangial cells
produce IL-12 mRNA and protein after lipopolysaccharide or tumor necrosis
factor-
stimulation
(19). Mesangial cells also
express the IL-12 ß1 chain receptor and respond directly to IL-12
stimulation by production of platelet-activating factor and reactive oxygen
species (19). Therefore, in
addition to the critical role for IL-12 in directing nephritogenic Th1
responses, IL-12 produced by intrinsic renal cells has the capacity to act as
an effector cytokine in crescentic GN.
The current studies evaluated the capacity of IL-12 produced by intrinsic renal cells to act as a local effector molecule in Th1-dependent cell-mediated renal inflammation by studying the development of crescentic GN in "IL-12 chimeric" mice with absent intrinsic renal cell IL-12 production but normal IL-12 production from bone marrow-derived immune/inflammatory cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bone Marrow Transplantation
Five- to 6-wk-old male recipient IL-12 -/- or C57BL/6 mice received 1100
rads of total body irradiation. Bone marrow cells were harvested aseptically
from the femora and tibiae of SPF WT donor mice, and red blood cells were
lysed. Recipient mice received 5 x 106 nucleated cells
intravenously within 6 h of irradiation. Mice were maintained under SPF
conditions for 8 wk to allow bone marrow reconstitution.
Assessment of Bone Marrow Engraftment and Lymphocyte Subset
Reconstitution
Circulating leukocyte numbers and lymphocyte subsets were assessed 8 wk
after bone marrow transplantation.
Circulating Leukocyte Numbers. Blood was collected into 3.3% sodium citrate, and circulating leukocyte numbers were determined by counting in a hemocytometer after lysis of red blood cells.
Circulating Lymphocyte Subsets. Citrated blood was incubated with FITC-conjugated anti-mouse CD4, anti-mouse CD8, and anti-B220 monoclonal antibodies (mAb; PharMingen, San Diego, CA), and lymphocyte subsets were quantified by flow cytometry, as described previously (21).
Lymphocyte Subset and Macrophage Repopulation in the Spleen. Splenic tissue was fixed in periodate/lysine/paraformaldehyde for 4 h, washed in 7% sucrose, frozen in liquid nitrogen, and stored at -70°C. Tissue sections (6 µm) were stained to demonstrate T cells and macrophages using a three-layer immunoperoxidase technique as described previously (3). The primary antibodies were GK1.5 (anti-mouse CD4 mAb, American Type Tissue Culture Collection [ATCC], Manassas, VA) and M 1/70 (anti-mouse Mac-1 mAb, ATCC).
Induction of GN
Anti-GBM globulin was prepared from serum of a sheep immunized against a
particulate fraction of mouse GBM as described previously
(22). Male WT,
IL-12—deficient (IL-12 -/-), bone marrow transplanted WT (sham
chimeric), and bone marrow transplanted IL-12 -/- (IL-12 chimeric) mice, all
13 to 14 wk of age, were sensitized by subcutaneous injection of 100 µg of
sheep globulin in 100 µl of CFA. Ten d later, GN was initiated by
intravenous administration of 4.4 mg sheep anti-mouse GBM globulin. The
development of GN was assessed 10 d after administration of anti-GBM
globulin.
Histologic Assessment of Glomerular Injury
Glomerular Crescent Formation. Kidney tissue was fixed in Bouin's
fixative and embedded in paraffin, and 3- µm sections were stained with
periodic acid-Schiff (PAS) reagent. Glomeruli were considered to exhibit
crescent formation when two or more layers of cells were observed in Bowman's
space. A minimum of 50 glomeruli were assessed to determine the crescent score
for each animal.
Glomerular T-Cell and Macrophage Accumulation. Kidney tissue was fixed in periodate/lysine/paraformaldehyde, sectioned, and stained in an identical manner as that described for spleen to demonstrate CD4+ T cells and macrophages. A minimum of 20 equatorial sectioned glomeruli were assessed per animal, and results were expressed as cells per glomerular cross section (c/gcs).
Tubulointerstitial Infiltration. The number of interstitial cells was counted by means of a 10-mm2 graticule fitted in the eyepiece of the microscope. Five randomly selected cortical areas, which excluded glomeruli, were counted for each animal. Each high-power field represented an area of 1 mm2, and counts were performed in a blinded protocol. Data are expressed as cells/mm2 and represent the mean ± SEM for animals in each group.
Functional Assessment of Glomerular Injury
Mice were housed individually in cages to collect urine before
administration of anti-GBM globulin and over the final 24 h of the experiment.
Urinary protein concentrations were determined by a modified Bradford method
(23). Serum creatinine
concentrations were measured by the alkaline picric acid method using an
autoanalyzer (Cobas Bio, Roche Diagnostic, Basel, Switzerland).
Histologic Demonstration of IL-12 Expression
Cryostat cut snap-frozen kidney tissue sections (6 µm) were stained for
IL-12 and macrophages by direct immunofluorescence using mAb conjugated with
Alexa Fluor dyes. Rat anti-mouse IL-12 mAb (anti—IL-12 p40, clone 15.6,
a gift of Dr. G. Trinchieri, Wistar Institute, Philadelphia, PA) was
conjugated with Alexa Fluor 594 dye (Molecular Probes, Eugene, OR, absorption
590 nm, and fluorescence emission 617 nm equivalent to the spectra for Texas
Red). Rat anti-mouse macrophage mAb M 1/70 was conjugated with Alexa Fluora
dye 488 (Molecular Probes, absorption 494 nm, and fluorescence emission 519 nm
equivalent to the spectra for FITC). Staining of tissue from
IL-12—deficient mice provided a negative control. Sections were
incubated concurrently with both antibodies at a final dilution of 1:50 for 60
min at room temperature and were examined by confocal microscopy. Confocal
images were collected using a confocal inverted Nikon Diaphot 300 microscope
(Bio-Rad, Hercules, CA) equipped with an air-cooled 25-mWat argon/krypton
laser with lines at 488, 586, and 647 nm and triple dichroic and 560 dichroic
long pass filter sets. Digital images were produced from an average of 8-line
scans of approximately 1 s duration with the oil immersion lens x40 and
were collected by using a Pentium 90 computer scan control and the image
acquisition and image analysis software packages COSMOS (Bio-Rad).
Assessment of the Systemic Immune Response to Sheep Globulin
Cutaneous DTH. Sensitized mice that developed GN were challenged 24
h before the end of the experiment by intradermal injection of 500 µg of
sheep globulin in 50 µl of phosphate-buffered saline into the plantar
surface of a hind footpad. A similar dose of an irrelevant antigen (Ag; horse
globulin) was injected into the opposite footpad as a control. Footpad
swelling was quantified 24 h later using a micrometer. Ag-specific DTH was
taken as the difference in skin swelling between sheep globulin— and
horse globulin—injected footpads and expressed 
footpad thickness
(mm).
Measurement of Circulating Mouse Anti-Sheep Antibody. Mouse anti-sheep globulin antibody (Ab) titers were measured by enzyme-linked immunosorbent assay on serum collected at the end of each experiment as described previously (7). Serial dilutions of serum were assayed using sheep globulin (10 µg/ml) as the capture Ag and horseradish peroxidase—conjugated sheep anti-mouse Ig Ab (Amersham, Little Chalfont, UK) as the detecting Ab.
Statistical Analyses
Assessment of bone marrow engraftment by analysis of circulating lymphocyte
subsets was performed on two separate occasions in a total of 11 IL-12
chimeric and 8 sham chimeric mice. Age-matched WT mice (n = 6) served
as controls. The development of GN was studied in groups of WT, IL-12
chimeric, and sham chimeric mice on two separate occasions and on a single
group of IL-12 -/- mice. All mice were males between 13 and 14 wk of age. The
total numbers of mice with GN in each group were as follows: WT, n =
6; IL-12 chimera, n = 8; sham chimera n = 5; and IL-12 -/-,
n = 4. Results are expressed as the mean ± SEM. The
statistical significance was determined by one-way ANOVA, followed by Fisher's
protected least significant difference post hoc analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12—deficient mice showed attenuation of DTH to the nephritogenic antigen as indicated by significantly reduced cutaneous swelling after an intradermal challenge with sheep globulin (IL-12 -/-, 0.28 ± 0.03 mm; WT, 0.81 ± 0.07 mm; P < 0.001). The serum titers of autologous anti-sheep globulin Ab were similar in WT- and IL-12—deficient mice (Figure 5), indicating that the humoral immune response to the nephritogenic antigen was unaffected by IL-12 deficiency.
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"Chimeric" IL-12 Mice Have Normal Lymphocyte Subsets and
Normal Systemic Immune Responses to Sheep Globulin
Bone marrow engraftment, studied 8 wk after transplantation, demonstrated
that circulating white blood cell numbers, T-cell subsets, and B cells in
IL-12 and "sham" chimeras were equivalent to those in WT mice
(Table 1). Their splenic architecture with regard to distribution of
CD4+ T cells and macrophages was normal (data not shown). After
cutaneous sensitization and intravenous administration of sheep globulin,
IL-12 and sham chimeric mice showed identical systemic immune responses to the
nephritogenic antigen as WT mice. The serum levels of mouse anti-sheep
globulin Ab were identical (Figure
5, and cutaneous DTH after antigen challenge in IL-12 chimeras
(Ag-specific skin swelling, 0.74 ± 0.05 mm) was equivalent to that in
WT (0.81 ± 0.07 mm) and sham chimeric mice (0.66 ± 0.05 mm).
This indicated functional restoration of immune competence in engrafted mice
and suggests that IL-12 production by non—bone marrow—derived
cells is not required for the full expression of these humoral and cell
mediated systemic responses.
IL-12 Production by Intrinsic Renal Cells Is Required for Full
Expression of Crescentic GN
Sham chimeric mice developed crescentic GN, with similar histologic
features to WT mice with GN, indicating that bone marrow transplantation
per se did not affect the development of this disease. The incidences
of crescentic glomeruli (WT, 31 ± 3%; sham chimeras, 33 ± 1%)
and glomerular infiltration of CD4+ T cells (WT, 1.2 ± 0.1
c/gcs; sham chimeras, 1.1 ± 0.05 c/cgs) and macrophages (WT, 3.3
± 0.4 c/gcs; sham chimeras, 3.2 ± 0.1 c/gcs) were equivalent
(Figure 3). Similarly, there
was no difference in functional renal injury between the two groups, indicated
by proteinuria (WT, 3.9 ± 0.8 mg/24 h; sham chimeras, 4.6 ± 0.1
mg/24 h) and serum creatinine (WT, 35 ± 3 µmol/L; sham chimeras, 36
± 6 µmol/L). The interstitial inflammatory injury was equivalent
(WT, 141 ± 4.2 cells/mm2; sham chimeras, 147 ± 5.5
cells/mm2; Figure
4).
However, despite equivalent systemic immune responses to the nephritogenic antigen to WT and sham chimeric mice, IL-12 chimeric mice developed significantly attenuated crescentic GN, indicating that IL-12 from intrinsic renal cells is required for full expression of immune renal injury in this model. IL-12 staining in the chimeric mice demonstrated localization of IL-12 expression on the surface of intraglomerular macrophages and limited expression in areas immediately surrounding these macrophages. Periglomerular macrophages did not express IL-12, and IL-12 expression was not detected in the tubules (Figure 2E). Histologic appearances of crescentic GN were attenuated (Figure 1E), and the incidence of crescentic glomeruli was significantly reduced (IL-12 chimeras, 16 ± 0.6%; P < 0.0001 compared with WT and sham chimeras). Glomerular accumulation of CD4+ T cells (IL-12 chimeras, 0.7 ± 0.1 c/gcs; P < 0.0001) and macrophages (IL-12 chimeras, 1.7 ± 0.2 c/gcs; P < 0.0001) was reduced compared with both WT and sham chimeric mice with GN (Figure 3). Proteinuria was reduced in IL-12 chimeras (1.9 ± 0.4 mg/24 h; P < 0.01) compared with WT and sham chimera. Serum creatinine levels in IL-12 chimeras with GN (26 ± 1 µmol/L; P < 0.05) were significantly reduced compared with WT sham chimeric mice with GN (Figure 4). The interstitial inflammatory infiltrate in IL-12 chimeric mice (IL-12 chimeras, 132 ± 5.0 cells/mm2) was not significantly reduced compared with WT and sham chimeric mice (Figure 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12 production by nonimmune cells has been demonstrated in a variety of organs, including the kidney (6, 18) and skin (28, 29). However, the contribution of IL-12 production by these nonimmune cells to organ-specific immune injury is unknown. This issue was addressed in a model of immune renal injury by using IL-12 chimeric mice, created by transplantation of normal bone marrow cells in to IL-12—deficient mice. These chimeric mice had normal circulating leukocytes and lymphocyte subsets and normal splenic architecture with regard to CD4+ T-cell and macrophage distribution. Their baseline proteinuria, serum creatinine, and renal histology were normal, indicating no protracted effects on the kidney, 8 wk after irradiation. Serum Ab titers and cutaneous DTH to the nephritogenic Ag were not different, indicating similar systemic immune responses in each group. The observation that antigen-specific skin swelling was not affected in IL-12 chimeric mice indicates that IL-12 expression by non—bone marrow—derived cells in the skin, e.g., keratinocytes, is not required for development of cutaneous DTH. This is consistent with the view that the major effector cells of cutaneous DTH are bone marrow—derived Langerhans cells, CD4+ T cells, and macrophages.
Crescent formation, glomerular inflammatory cell influx, and functional
renal injury were significantly reduced, indicating that IL-12 from intrinsic
renal cells makes a significant contribution to the effector phase of this
disease. IL-12 expression was demonstrated in glomeruli and tubules of WT and
sham chimeric mice with GN. In glomeruli, IL-12 was demonstrated on the
surface of and adjacent to macrophages. IL-12 expression was also observed in
areas of glomeruli remote from macrophages, consistent with production by
intrinsic glomerular cells. Mesangial cells have been demonstrated to express
IL-12 p40 mRNA and p70 protein in response to proinflammatory stimuli,
including tumor necrosis factor- and lipopolysaccharide
(19). Periglomerular and
interstitial macrophages showed minimal IL-12 expression, suggesting they may
have a different activation status and different functions to intraglomerular
macrophages.
In IL-12 chimeric mice, IL-12 expression was restricted to the surface of macrophages and their immediate surrounds. IL-12 expression was not observed in tubules and the interstitial inflammatory infiltrate was not attenuated, indicating that this infiltrate is not dependent on tubular IL-12 production. Theses studies provide the first demonstration of an important functional role for a cytokine derived from nonimmune intrinsic renal cells in immune renal injury. GN in IL-12 chimeric mice was not reduced to the extent seen in IL-12—deficient mice, indicating that the role of local IL-12 production is complementary to that of bone marrow—derived cell IL-12 production.
IL-12 from intrinsic renal cells may act in an autocrine or a paracrine manner to amplify immune renal injury. Mesangial cells have been demonstrated recently to express the IL-12 receptor and respond to IL-12 in vitro by increasing production of inflammatory mediators, platelet activating factor, and reactive oxygen species (19), consistent with an autocrine role for mesangial cell—derived IL-12 in crescentic GN. Paracrine effects of IL-12 may be exerted on intraglomerular T cells and macrophages or endothelial cells. The potential for IL-12 to increase expression of intracellular adhesion molecule 1 or E-selectin (30) or to increase production of chemokines and RANTES has been demonstrated in other diseases (31,32).
Intrinsic renal cell expression of major histocompatibility complex II was
demonstrated recently to be required for renal recruitment of T cells in this
model of crescentic GN (33),
and simultaneous expression of IL-12 by these intrinsic cells may augment Th1
activation and proinflammatory effector functions of these T cells after
recruitment. IL-12 has been shown to promote Th1 development, stimulate Th1
cell proliferation, and induce IFN- production by resting and activated
T cells
(34,35,36).
IFN- stimulates the release of monocyte chemotactic protein-1
(37) and production of
proinflammatory cytokines, including IL-12
(16). IL-12—deficient
mice have deficient IFN- production
(20), and IFN- has been
demonstrated to be an important proinflammatory mediator in crescentic GN
(4,7).
However, one report suggests that the absence of the IFN- receptor does
not alter crescent formation in anti-GBM nephritis
(38).
In summary, these studies demonstrate that IL-12 production by non—bone marrow—derived cells is required for the full expression of a Th1-dependent model of immune renal injury but not for cutaneous DTH. They provide the first demonstration of the capacity of a cytokine derived from intrinsic renal cells to augment immune renal injury and suggest that IL-12 production by intrinsic renal cells, demonstrated in vitro and in human GN (39), may be an important modulator of renal injury.
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Acknowledgments |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mediates
crescent formation and cell-mediated immune injury in murine
glomerulonephritis. J Am Soc Nephrol10
: 752-759,1999 production and type 1 cytokine responses.
Immunity 4:471
-481, 1996[Medline]
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), sham chimeric
(
), IL-12 chimeric ([UNK]), and IL-12—deficient (
) mice
developing crescentic glomerulonephritis. A titration of normal mouse serum
(
) is shown for comparison.