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Endocrinology Vol. 138, No. 12 5220-5226
Copyright © 1997 by The Endocrine Society

ARTICLES

Interferon-{gamma} Potentiates Interleukin (IL)-6 and Tumor Necrosis Factor-{alpha} But Not IL-1ß Induced by Endotoxin in the Brain

M. G. De Simoni, L. Terreni, R. Chiesa, F. Mangiarotti and G. L. Forloni

Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy

Address all correspondence and requests for reprints to: Dr. Maria Grazia De Simoni, Istituto Mario Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail: de-simoni{at}irfmn.mnegri.it


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Because interferon-{gamma} (IFN{gamma}) is present in the central nervous system during neurologic diseases associated with inflammation, its effect on endotoxin-induced cytokines was studied. Cerebrospinal fluid (CSF) and serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-{alpha} (TNF{alpha}), their messenger RNA expression in brain areas (hypothalamus, hyppocampus, and striatum) and in spleen were evaluated 2 and 8 h after endotoxin [lipopolysaccharide (LPS), 25 µg/rat icv], IFN{gamma} (2.5 µg/rat icv) or after their coadministration in rats. CSF and serum IL-1ß levels were increased by LPS alone and IFN{gamma} coadministration did not furtherly increase them. IFN{gamma} potentiated LPS effect on IL-6 and TNF{alpha} levels in both CSF and serum. LPS and IFN-{gamma} coadministration did not alter IL-1ß messenger RNA expression induced by LPS in brain areas and in spleen, but it potentiated that of IL-6 and TNF{alpha}. The present in vivo data show that icv coadministration of LPS and IFN{gamma} results in a potentiation of cytokine production (IL-6 and TNF{alpha}) which may trigger a cascade of events relevant to neurodegenerative processes. This action is independent of IL-1ß because the production of this cytokine is not altered by IFN{gamma} treatment.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INCREASED concentrations of several inflammatory cytokines have been observed in brain tissue and cerebrospinal fluid (CSF) of several neurodegenerative diseases. They include Alzheimer disease (1, 2), Down syndrome (3), epilepsy (4), Parkinson’s disease (5, 6), and multiple sclerosis (7, 8, 9). High levels of inflammatory molecules are also found in central nervous system (CNS) conditions such as stroke (10, 11) or HIV dementia (12, 13), where neurodegeneration is present. Whether these inflammatory molecules are causal in the neurodegenerative process or secondary to it and which is their role in neuronal survival and damage is still not known. One distinctive feature of these immune molecules is that they act in cascade stimulating and inhibiting one another production and action. A crucial question concerns the initial stimuli triggering the production of different cytokines that are simultaneously present in neurodegenerative conditions.

The brain constitutively expresses inflammatory cytokines such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor-{alpha} TNF{alpha}, and several in vitro and in vivo animal models show that different stimuli activate microglia and astrocytes resulting in overproduction of these cytokines (14, 15). Another cytokine for which a role has been proposed in neurodegenerative diseases is interferon-{gamma} (IFN{gamma}) (12, 16, 17, 18, 19, 20). Unlike the cytokines mentioned above, it is generally believed that there is no endogenous cell source of IFN{gamma} in the normal brain and this cytokine is present in the CNS only during disease states when activated T cells or macrophages have infiltrated the brain. In these conditions, high levels of IFN{gamma} have been reported in brain tissue although the actual amount has not been measured (16, 21). Little is known of IFN{gamma} actions in the brain although it is believed to activate a local immune response. In vitro studies have shown that IFN{gamma} can modulate gene expression in astrocytes and microglia (16, 17, 22). Moreover, it can induce expression of both class II MHC antigens and ICAM-1 on astrocytes and microglia, which can contribute to the ability of these cells to act as antigen-presenting cells in the CNS and stimulate aberrant immune responses within this site (16).

The present study evaluates whether in vivo, in the CNS, similarly to what observed in the periphery, IFN{gamma} may act as an activating signal for inflammatory cytokine production. The effect of IFN{gamma} intracerebroventricular (icv) administration was investigated on IL-1ß, IL-6 and TNF{alpha} induced by endotoxin [lipopolysaccharide (LPS), a potent trigger of these cytokines (23, 24, 25)]. CSF levels of these cytokines as well as their messenger RNA (mRNA) expression in brain areas (striatum, hypothalamus, and hippocampus) were evaluated. Moreover, because central LPS efficiently induces inflammatory cytokines in the periphery, serum production of the same cytokines as well as their expression in spleen, were also investigated.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Procedures involving animals and their care were conducted in conformity with institutional guidelines that are in compliance with national [Decreto Legislativo (D.L.) No. 116, Gazzetta Ufficiale (G.U.) Supplement No. 40, 18 February, 1992) and international laws and policies (EEC Council Directive 86/609, OJ L 358,1; Dec. 12, 1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publication No. 85–23, 1985). Male Sprague-Dawley rats (Caesarean Derived-Caesarean Originated Barrier Sustained, Charles River, Calco (L.C.), Italy, 250–300 g) were used. They were housed with free access to food and water, under a 12 h light/dark cycle with constant temperature (21–23 C) and humidity (60 ± 5%).

LPS administration
One polyethylene cannula was permanently implanted in the lateral ventricle (23) 3 days before treatment. LPS (25 µg/6 µl·rat; phenol-extracted preparation from Escherichia coli 055: B5, Sigma Chemical Co., St. Louis, MO), dissolved in sterile pyrogen-free saline, rat recombinant IFN{gamma} (2.5 µg/6 µl·rat corresponding to 2.75 x 104 U; Roussel Uclaf, Romainville, France), dissolved in 0.1% BSA, and vehicle were administered icv. Data refer to one of three independent experiments, yielding the same results.

Because an in vivo central action of IFN{gamma} has not been widely investigated before and our aim was to explore a possible pathogenetic role of cytokines, we employed relatively high doses of LPS and IFN{gamma}. In previous in vivo studies, similar concentrations of IFN{gamma} were used to produce inflammatory conditions (26). High LPS doses have been used to mimic stressful conditions (27) or to activate cytokine production and the HPA axis (25).

CSF, serum, and tissue samples
Two and eight hours after treatment, rats were anesthetized with chloral hydrate, 350 mg/kg ip, and CSF (60–100 µl) was drawn from the cisterna magna using a glass capillary with a tip of approximately 300 µm. A careful surgery allowed to avoid blood contamination. Immediately after, the rats were decapitated and trunk blood was collected in sterile tubes. Serum was prepared by centrifugation at 15,000 x g for 5 min. CSF and serum were divided up for IL-1ß enzyme-linked immunosorbent assay (ELISA), IL-6 and TNF{alpha} bioassays. Samples were stored at -20 C until assay.

Spleen and brain areas (hypothalamus, hippocampus, and striatum) were dissected. Tissues were immediately frozen on dry ice and kept at -20 C until mRNA extraction for Northern blot analysis.

IL-1ß ELISA
IL-1ß was measured in CSF and in serum by a two-site ELISA as described by Garabedian et al. (28), except that the color was developed using avidin-peroxidase (Sigma) and 2, 2’-azino-di[3-ethyl-benzthiazoline sulfonate (6)] peroxidase substrate system (KPL, Gaithersburg, MD) as chromogen. Absorbance was read at 405 nm. The detection limit was 3.9 pg/ml.

IL-6 bioassay
IL-6 was measured in CSF and in serum as hybridoma growth factor using the 7TD1 as previously described (29). Results are expressed as units/ml in comparison with a reference curve obtained in each experiment using recombinant human IL-6 (Immunex, Seattle, WA). Reference curves obtained were comparable in all experiments. One unit in the 7TD1 assay corresponded to 1 pg human recombinant IL-6. The sensitivity of the assay with rat serum is 50 U/ml.

TNF{alpha} bioassay
CSF and serum TNF{alpha} was measured by cytotoxicity on L929 cells in the presence of 1 µg/ml of actinomycin D as previously described (30). TNF{alpha} levels were calculated using recombinant human TNF{alpha} (BASF/Knoll, Ludwigshafen, Germany; specific activity 107 U/mg) and expressed as ng/ml. The sensitivity of the bioassay was 5 pg/ml.

RNA extraction and Northern blot analysis
RNA was extraced from tissue samples according to the acid guanidinium-phenol-chlorophorm procedure described previously (23). Total RNA was separated on 1.2% agarose-formaldehyde gels and transferred to Nylon 66 filters (Gene Screen Plus, Dupont, Raketstraat, Belgium). Based on spectrophotometric analysis, an equal amount of total RNA was applied to each lane (15–20 µg). The membranes were hybridized with the following probes (23): 1) ß-actin mRNA probe corresponding to a 0.8-kb fragment from a human complementary DNA (cDNA) clone (31); 2) IL-1ß mRNA probe corresponding to a 1.3-kb fragment from mouse cDNA (32); 3) IL-6 mRNA probe corresponding to a 0.65-kb fragment from mouse cDNA (33); 4) TNF{alpha} mRNA probe corresponding to a 0.45-kb from human cDNA (34). Probes were labeled using a randomly primed DNA labeling kit from Amersham and 32P-dCTP. All labeled probes were purified through Quick Spin Columns (Boehringer Mannheim SpA, Monza, Italy). After O/N hybridization with the appropriate 32P-labeled cDNA probe, blots were exposed to x-ray films at -80 C with intensifying screens, for the time needed to obtain a signal in a linear range. The exposure time for a given probe was the same in all experiments. Densitometric analysis of autoradiograms was done with an IBAS 2 image analyzer (Kontron-Zeiss, Milano, Italy), integrating the optical density with the area of the hybridized bands (35). The signal associated with the presence of ß-actin mRNA was used as an internal standard to normalize IL-1ß, IL-6, and TNF{alpha} expression.

The IL-6 probe identifies two different mRNAs of 1.2- and 2.4-kb (22, 25). The 1.2-kb band is predominant in either the CNS or spleen, whereas the 2.4 kb band was not always detectable in our experiments. We therefore evaluated only the signal corresponding to the 1.2-kb transcript.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
CSF and serum cytokine levels
To determine whether IFN{gamma} affected LPS-induced cytokine production, the two drugs were administered alone or simultaneously and CSF and serum IL-1ß, IL-6 and TNF{alpha} levels were measured. Neither saline nor IFN{gamma} administered alone induced detectable cytokine levels. As shown in Fig. 1Go, LPS efficiently induced CSF and serum IL-1ß (Fig. 1Go, A and B). In the CSF, the effect was higher 8 h after the treatment, whereas in serum the maximal effect was observed at 2 h. The simultaneous administration of IFN{gamma} did not further increase IL-1ß production in both CSF and serum. The results in Fig. 2Go show that IFN{gamma} coadministration potentiated LPS-induced IL-6. This effect was observed at 8 h in the CSF, whereas it was maximal at 2 h but still present at 8 h, in serum. We next investigated whether IFN{gamma} increased LPS-induced TNF{alpha}. As shown in Fig. 3Go, LPS effect was maximal at 2 h in both CSF and serum. IFN-{gamma} induced an increase in LPS-induced TNF{alpha} both in the CSF (Fig. 3AGo) and in serum (Fig. 3BGo).



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  		Figure 1. CSF (A) and serum (B) IL-1ß levels 2 and 8 h after LPS (25 µg/rat, icv) and IFN{gamma} (2.5 µg/rat, icv) administered alone or simultaneously (mean ± SE, n = 5–6).

 


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  		Figure 2. CSF (A) and serum (B) IL-6 levels 2 and 8 h after LPS (25 µg/rat icv) and IFN{gamma} (2.5 µg/rat, icv) administered alone or simultaneously (mean ± SE, n = 5–6); **, P < 0.01 vs. LPS alone, Student’s t test.

 


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  		Figure 3. CSF (A) and serum (B) TNF{alpha} levels 2 and 8 h after LPS (25 µg/rat icv) and IFN{gamma} (2.5 µg/rat, icv) administered alone or simultaneously (mean ± SE, n = 5–6); **, P < 0.01 vs. LPS alone; *, P < 0.05 vs. LPS alone, Student’s t test.

 
Cytokine mRNA expression
To determine whether IFN{gamma} affected LPS-induced cytokine expression, the two drugs were administered alone or simultaneously and IL-1ß, IL-6, and TNF{alpha} mRNA were measured. Neither saline nor IFN{gamma} administered alone induced a detectable signal in the brain areas considered and in spleen (Fig. 4Go). LPS significantly induced IL-1ß in the brain areas considered as well as in the spleen, although with a different time-course. Similar to what observed for cytokine levels, when LPS and IFN{gamma} were injected simultaneously, no differences were observed in IL-1ß mRNA expression (Fig. 5Go). LPS increased IL-6 expression in the brain areas and in the spleen. This increase was significantly potentiated by IFN{gamma} coadministration (Fig. 6Go). The effect was greater at 8 h in striatum and hippocampus, whereas in hypothalamus the increase observed at the two time points was similar. In the spleen the maximal mRNA expression was observed at 2 h. TNF{alpha} mRNA expression was significantly increased by LPS and IFN{gamma} coadministration in brain areas and in spleen (Fig. 7Go). The pattern of expression in striatum and hippocampus was similar to what observed for IL-6, the effect being maximal at 2 h in both hypothalamus and spleen.



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  		Figure 4. Examples of Northern blot with mRNA extracted from hippocampus (A) and spleen (B) of rats treated with LPS (25 µg/rat, icv) and IFN{gamma} (2.5 µg/rat, icv) administered alone or simultaneously. They were hybridized with ß-actin, IL-1ß, IL-6, and TNF{alpha} probes.

 


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  		Figure 5. IL-1ß mRNA expression in brain areas and in spleen 2 and 8 h after LPS (25 µg/rat, icv) and IFN{gamma} (2.5 µg/rat, icv) administered alone or simultaneously (mean ± SE, n = 5–6).

 


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  		Figure 6. IL-6 mRNA expression in brain areas and in spleen 2 and 8 h after LPS (25 µg/rat, icv) and IFN{gamma} (2.5 µg/rat icv) administered alone or simultaneously (mean ± SE, n = 5–6); **, P < 0.01 vs. LPS alone; *, P < 0.05 vs. LPS alone, Student’s t test.

 


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  		Figure 7. TNF{alpha} mRNA expression in brain areas and in spleen 2 and 8 h after LPS (25 µg/rat, icv) and IFN{gamma} (2.5 µg/rat, icv) administered alone or simultaneously (mean ± SE, n = 5–6); **, P < 0.01 vs. LPS alone; *, P < 0.05 vs. LPS alone, Student’s t test.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Cytokine induction in the brain and periphery
Central LPS administration is a potent trigger for inflammatory cytokines in the brain. Two hours after LPS injection, TNF{alpha}, IL-6, and IL-1ß were clearly detectable in CSF. Differently from TNF{alpha}, whose turnover is more rapid, high levels of IL-6 and IL-1ß were still present 8 h after injection. Although the cytokines considered are constitutively expressed in the brain (14), the sensitivity of the Northern blot analysis did not allow to detect a signal in control or IFN{gamma}-treated rats. LPS clearly induced mRNA expression for IL-1ß, IL-6, and TNF{alpha} in the three brain areas considered. Except for TNF{alpha} expression in hypothalamus, the induction of mRNA was still evident 8 h after the treatment, in some cases the induction being higher than at the shorter time. It may only be hypothesized that the somewhat different time-course of cytokine induction in the three brain areas is related to a specific, unexplored role of the cytokine in that area (23).

For each cytokine, the pattern of mRNA induction and that of its presence in CSF were similar. This indicates a close temporal relation between expression and production suggesting that cytokines are synthesized, rapidly secreted, and accumulated in the CSF. It should only be mentioned that the time-course of TNF{alpha} in CSF is better explained by the pattern of mRNA expression in hypothalamus than by the other two brain areas considered.

The present data confirm and extend previous findings showing that centrally administered LPS efficiently induces inflammatory cytokines not only in the brain tissue but also in the periphery. Because LPS is a lipophilic molecule, it may leak from the brain to the periphery. However, the observation that icv LPS induces more marked and lasting effects in the brain than the periphery indicated that it does not leave the central compartment in significant amounts (36). What was previously observed for IL-6 and IL-1ß (23) also applies to TNF{alpha}. Icv LPS in fact caused rapid induction of the three cytokines considered, evident on the expression and on synthesis, with a time-course different from that in the brain. Whereas the effect in the CNS was slower and longer lasting, it was rapid and transient in the periphery, suggesting different regulatory mechanisms.

IFN{gamma} effect on LPS-induced cytokines
The present data show for the first time in vivo that IFN{gamma} acts in the brain as an activating signal for brain cells, rendering them more responsive to LPS stimuli. Because IFN{gamma} induced no change in the cytokines considered or in their message, we assumed that no significant contamination was present. Although IFN{gamma} did not induce cytokine synthesis and production when administered alone, it markedly potentiated LPS action. This was evident on IL-6 and TNF{alpha} expression and production, in the brain and in the periphery.

Unlike IL-6 and TNF{alpha}, IFN{gamma} was completely ineffective in modulating IL-1ß expression and production in the brain and periphery, indicating that this cytokine is regulated independently from the other two. However, synergy with IL-1ß might be achieved at lower doses of LPS or IFN{gamma}. Although IL-6 and TNF{alpha} induction by LPS may be mediated by IL-1ß, the results suggest that IFN{gamma} stimulates IL-6 and TNF{alpha} synthesis independently from IL-1ß.

Much of the knowledge regarding the mechanism triggered by IFN{gamma} and LPS comes from studies on immune cells. In monocytes and macrophages IFN{gamma} was reported to interact directly with the CD14, the LPS receptor (37). This does not seem to be the case in the present experimental model because in that case LPS and IFN{gamma} coadministration should cause similar changes in all the cytokines considered. Studies on gene regulation in macrophages activated by IFN{gamma} and LPS have shown that IFN{gamma} enhances LPS-initiated transcription of TNF{alpha} and not its stability (38, 39). The present observation that increased mRNA accumulation closely corresponds to increase in the protein synthesis indicates that the steady-state of TNF{alpha} and IL-6 message is not affected.

IFN{gamma}’s effect on brain cells has been the subject of several in vitro studies. IFN{gamma} has been proposed to inhibit LPS-induced IL-1ß and IL-6 (40) or to potentiate TNF{alpha} induction (18) in microglial cells. Other reports indicate that exposure of astrocytes to IFN{gamma} renders them responsive to a suboptimal dose of LPS resulting in a significant stimulation of TNF{alpha} production (17). Actually, the cell source of cytokines produced in the present animal model is still to be clarified.

The pathogenetic role of IFN{gamma} in neurologic diseases is not known. High levels of IFN{gamma} are found in the brain tissue of multiple sclerosis patients (7, 8, 9). The possible relevance of IFN{gamma} in the pathogenesis of Alzheimer’s disease is proposed in studies showing that ß-amyloid synergizes with IFN{gamma} in triggering the production of reactive nitrogen intermediates and TNF{alpha} in microglial cells and in mediating neuronal injury (18, 19). IFN{gamma} is present in the CNS during other neurological diseases associated with inflammation including viral meningitis, encephalitis, HIV dementia, and in animal models of CNS disease such as experimental allergic encephalomyelitis (15). Associated with these neurological diseases is an inflammatory infiltrate in the CNS composed of activated macrophages, B and T lymphocytes, the last cell type being the potential local source of endogenous IFN{gamma}.

There is increasing evidence that inflammatory cytokines including TNF{alpha} and IL-6 play a pathogenetic role in CNS conditions. For example, anti-TNF{alpha} antibodies are protective in animal models of cerebral malaria (41). TNF{alpha} is a potent stimulus for nitric oxide, a mediator of ischemic brain damage (42, 43, 44). Transgenic mice overexpressing IL-6 or TNF{alpha} in the brain show neurodegeneration, astrocytosis, microgliosis, demyelinization, and macrophage accumulation (45, 46). The present data, showing that IFN{gamma} administration in the brain results in a potentiation of IL-6 and TNF{alpha} production, suggest that IFN{gamma} in the CNS may trigger a cascade of events relevant to neurodegenerative processes.


   Acknowledgments
 
R. Chiesa was a recipient of Istituto Scientifico Roussel Italia fellowship.

Received May 9, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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