help button home button Am J Pathol ASIP MEMBERSHIP
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Benigni, F.
Right arrow Articles by Ghezzi, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Benigni, F.
Right arrow Articles by Ghezzi, P.
(American Journal of Pathology. 1998;153:1377-1381.)
© 1998 American Society for Investigative Pathology

Short Communications

Intracerebroventricular Injection of Anti-Fas Activates the Hypothalamus-Pituitary-Adrenal Axis and Induces Peripheral Interleukin-6 and Serum Amyloid A in Mice

Comparison with Other Ligands of the Tumor Necrosis Factor/NerveGrowth Factor Receptor Superfamily

Fabio Benigni* , Silvano Sacco* , Luigi Aloe{dagger} and Pietro Ghezzi*

From the Laboratory of Neuroimmunology,* Mario Negri Institute for Pharmacological Research, Milano, and the Institute of Neurobiology,{dagger} Consiglio Nazionale delle Ricerche, Rome, Italy


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Fas is a receptor of the tumor necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily that mediates apoptosis and some inflammatory changes. As the central administration of TNF is known to activate the hypothalamus-pituitary-adrenal axis (HPAA) and to induce peripheral responses including induction of serum interleukin (IL)-6 and serum amyloid A (SAA), we investigated the effects of intracerebroventricular (i.c.v.) administration of agonist anti-Fas monoclonal antibody Jo2. Centrally administered anti-Fas (1 µg/mouse, i.c.v.) induced elevated levels of corticosterone, IL-6, and SAA comparable to those observed after i.c.v. administration of recombinant murine TNF. On the other hand, administration of murine NGF did not elevate serum corticosterone or IL-6, but induced SAA. Thus, Fas can trigger a centrally mediated anti-inflammatory response (HPAA activation) and induce a peripheral acute-phase response comparable to that induced with TNF, whereas NGF induces only acute-phase proteins.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Fas is a cell surface receptor belonging to the tumor necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily that mediates apoptotic death upon activation by Fas ligand or agonist antibodies.1,2 Lymphocyte-mediated apoptosis may play a role in a variety of autoimmune diseases,3 and Fas expression was recently reported in the brain of multiple sclerosis patients4 and was suggested to be involved in other diseases of the central nervous system.5 In addition to inducing apoptosis, Fas induces typical inflammatory changes, including increase of interleukin (IL)-6 and IL-8 secretion and activation of nuclear factor-{kappa}B.6,7

In vivo administration of Fas ligand or the agonist anti-Fas monoclonal antibody (MAb) Jo2 induces fulminant hepatitis8 and lethality in Propionibacterium acnes-pretreated mice.8,9

One of the main protective mechanisms against TNF-mediated systemic toxicity is represented by the activation of the hypothalamus-pituitary-adrenal axis (HPAA), resulting in an increase in serum corticosteroid levels.10,11 Several cytokines activate the HPAA, including IL-112 and TNF,13 whereas other cytokines, (IL-6, IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, and cardiotrophin-1) potentiate this induction.14

Activation of the HPAA, either by cytokines or stress, represents a negative feedback mechanism that inhibits the production of pro-inflammatory cytokines.11,15 In fact, adrenalectomized mice are extremely sensitive to cytokine-mediated lethality.16 Activation of the HPAA is also important in the recovery from experimental autoimmune encephalomyelitis,17,18 and an impairment of this response was associated with the susceptibility of Lewis rats to arthritis.19

Activation of the HPAA is not the only action of pro-inflammatory cytokines on the central nervous system. There is evidence that also induction of peripheral responses (IL-6 and liver acute-phase proteins) can be induced through a centrally mediated action. In fact, we previously reported that intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS), TNF,20 or IL-121 induces higher circulating levels of IL-6 than when the inducer is injected peripherally. It has also been known for a long time that centrally injected IL-1 induces a liver acute-phase response at doses that are ineffective when administered peripherally.22,23

In a recent study using agonist antibodies or knock-out mice, we have shown that activation of the HPAA and induction of peripheral IL-6 induced by i.c.v. injection of TNF is mediated primarily by TNF receptor (TNFR) p55.20 Due to the sequence homology and functional similarities between Fas and the TNFR p55,1 we investigated whether in the central nervous system Fas could mediate an activation of the HPAA and an induction of a peripheral acute-phase response.

For this purpose, we injected mice i.c.v. with the agonist anti-Fas MAb Jo2 and measured serum corticosterone levels. We also measured serum levels of IL-6 and of the liver acute-phase protein, serum amyloid A (SAA). In these experiments, the effect of anti-Fas was compared with that of murine recombinant (rm)TNF and murine nerve growth factor (NGF), which was was previously shown to induce acute-phase proteins in vivo.24


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and Treatments

Procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance with national (D.L. 116, G.U. supplement 40, 18 February, 1992, Circolare 8, G.U. Luglio 1994) and international laws and policies (EEC Council Directive 86/609, OJ L 358, 1, December 12, 1987; Guide for the Care and Use of Laboratory Animals, U.S. National Research Council, 1996).

Male CD-1 mice (25 g body weight) from Charles River Italia, Calco, Como, Italy, were used. Mice were housed five per cage and fed ad libitum. The agonist anti-Fas MAb Jo2 (a kind gift from Dr. Shigekazu Nagata, Osaka University Medical School, Osaka, Japan) was injected i.c.v. via a 28-gauge needle into ether-anesthetized mice25,26 at the dose of 1 µg/mouse. All i.c.v. injections were made in a final volume of 10 µl. At 90 minutes, 3 hours, or 24 hours after injection, blood was obtained from the retro-orbital plexus under light ether anesthesia, and serum was prepared. Control mice received saline alone or an irrelevant MAb (anti-human TNFR p55, a kind gift from Dr. Wim Buurman, University of Limburg, Maastricht, The Netherlands), as previously described.20 In some experiments, mice were injected i.c.v. with 1 µg of rmTNF (kind gift of Prof. Walter Fiers, Ghent, Belgium) or 2.5 µg of murine ß-NGF. Murine NGF (2.5S) was purified from the salivary gland of adult male mice following the procedure described by Bocchini and Angeletti.27 The concentration of pure NGF was determined by molar extinction, and the biological activity of the purified NGF was evaluated with the in vitro bioassay.28

Biochemical Determinations

Serum corticosterone was measured by a radioimmunoassay using an antiserum for corticosterone radioimmunoassay obtained from Sigma (C-8784; Sigma Chemical Co., St. Louis, MO) and following manufacturer's indications. [3H]Corticosterone was purchased from Amersham (Arlington Heights, IL).

SAA was measured by a previously described ELISA (Hemagen Diagnostics, Waltham, MA).

IL-6 was measured as hybridoma growth factor using 7TD1 cells (a kind gift from Dr. Jacques van Snick, Brussels, Belgium) as previously described.29 IL-6 activity is expressed as co-stimulatory units per milliliter using rIL-6 as a standard. The sensitivity of the assay was 50 U/ml.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mice received 1 µg of anti-Fas antibody and were bled at 1.5, 3, or 24 hours for corticosterone or IL-6 and at 24 hours for SAA, based on previous results showing that these are the optimal time points for the effects under investigation when cytokines are injected i.c.v. It should also be noted that anti-Fas-injected mice did not look sick within this time frame (i.e., 24 hours).

Figure 1 shows the effect of an i.c.v. injection of anti-Fas on serum corticosterone 1.5 and 3 hours after injection. Control mice received saline i.c.v. alone. For purpose of comparison, the effect of 1 µg of rmTNF (also given i.c.v.) is also shown. It can be seen that both rmTNF and anti-Fas augmented approximately two- to three-fold serum corticosterone levels. Co-administration of the two resulted in an additive effect, although no direct comparison of anti-Fas and rmTNF can be made in terms of dose. In two separate experiments we tested an irrelevant antibody, as described in Materials and Methods, at doses up to 6 µg/mouse, and did not see any augmentation of serum corticosterone compared with saline controls (data not shown), in agreement with previous reports.20



View larger version (34K):
[in this window]
[in a new window]
  		Figure 1. Central administration of anti-Fas activates the hypothalamus-pituitary-adrenal axis. Mice were treated i.c.v. with 1 µg of anti-Fas, rmTNF, or both, and serum corticosterone was measured 1.5 and 3 hours later. Data are presented as mean ± SD (n = 5). *P <0.05 versus saline alone by Duncan's test.

 
Figure 2 shows that i.c.v. injection of anti-Fas markedly induced serum IL-6 levels, to an extent comparable to that of rmTNF. The levels of IL-6 after anti-Fas were 3512 U/ml at 1.5 hours and 6432 U/ml at 3 hours; those after rmTNF were 4433 U/ml and 1505 U/ml 1.5 and 3 hours later, respectively. As for corticosterone, an additive effect was observed between anti-Fas and rmTNF. An irrelevant isotype MAb (see Materials and Methods), at doses up to 6 µg, did not induce any significant augmentation of serum IL-6 compared with saline controls (6 µg of {alpha}hTNFR p55 produced undetectable levels of serum IL-6, ie, <50 U/ml in one experiment and 149 ± 104 U/ml in a second experiment), in agreement with previous reports.20



View larger version (39K):
[in this window]
[in a new window]
  		Figure 2. Central administration of anti-Fas induces peripheral IL-6. Mice were treated i.c.v. with 1 µg of anti-Fas, rmTNF, or both, and serum IL-6 was measured 1.5 and 3 hours later. Data are presented as mean ± SD (n = 5). **P <0.01 versus saline alone by Duncan's test.

 
Under the experimental conditions described above, i.c.v. administration of murine NGF (2.5 µg/mouse) did not elevate serum corticosterone or IL-6 (data not shown).

As shown in Figure 3 , i.c.v. administration of anti-Fas antibody induced marked levels (50 µg/ml) of SAA 24 hours after treatment. The levels of SAA were very low after saline injection (7 µg/ml). Also, rmTNF and murine NGF induced marked levels of SAA.



View larger version (43K):
[in this window]
[in a new window]
  		Figure 3. Central administration of anti-Fas induces SAA. Mice were treated i.c.v. with 1 µg of anti-Fas, rmTNF, or 2.5 µg of mNGF, and SAA was measured in serum 24 hours later. Data are presented as mean ± SD (n = 5). **P <0.01 versus saline alone by Duncan's test.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our paper shows that one central effect of anti-Fas administration is to increase serum levels of corticosterone, IL-6, and SAA. Elevation of serum corticosterone might have various suppressive actions on the immune system and, in particular, inhibit the synthesis of several cytokines.10,11 Activation of the HPAA is generally viewed as an anti-inflammatory feedback response, but corticosteroids may have other actions, including induction of apoptosis in T cells.

Also, induction of IL-6 and SAA may be viewed as protective mechanisms. In fact, previous works have shown that induction of hepatic acute-phase proteins is important in the protective effect of IL-1 pretreatment against sepsis,30 and administration of acute-phase proteins or their overexpression in transgenic animals is protective against endotoxic shock or TNF-induced lethality.31,32 Another acute-phase protein, {alpha}2-macroglobulin, has a protective effect in animal models of experimental autoimmune encephalomyelitis.33

Furthermore, IL-6 might be regarded as protective. In fact, exogenous administration of IL-6 inhibits TNF production in vitro and in vivo34,35 and IL-6-deficient mice produce more TNF in response to endotoxin.35,36

The fact that TNF, but not NGF, share with Fas the ability to induce serum corticosterone and IL-6 is in agreement with the differences in the various receptors of the TNF/NGF superfamily. This superfamily includes the two TNF receptors, the low-affinity NGF receptors, and other members. However, whereas the extracellular amino acid sequence of the extracellular region is relatively conserved, the cytoplasmic region is not, and in this case the similarities are restricted to Fas and TNFR p55.37 If we consider that our previous work indicated that TNFR p55 is responsible for the central effects reported here,20 it is not surprising that the action of TNF is shared only by Fas and not NGF. The observed induction of acute-phase proteins after systemic24 or central (this paper) administration of NGF might therefore be mediated either by the peripheral NGF receptor or by a receptor subtype other than the low-affinity one which belongs to the TNFR family.

It should be noted that Fas shares with the receptors for IL-1 and TNF (IL-1RI and TNFR p55, respectively) a signaling cascade involving MAP3K kinase ultimately resulting in the activation of NF-{kappa}B,38 a transcription factor of particular importance in the inflammatory response. As IL-1 and TNF, like Fas, are activators of the HPAA, common pathways are likely candidates as the mediators implicated in these effects. It is, however, difficult to explain the lack of effect of NGF in our system within this frame, as controversial reports have indicated either that NGF activates NF-{kappa}B39 or that, unlike TNF, NGF does not activate this transcription factor in neural tissue.40,41

Thus, activation of the HPAA and induction of SAA seem to be a common feature of anti-Fas and TNF. It seems likely that the elevation of SAA by anti-Fas reported in this paper is mediated by IL-6, a key mediator of the acute-phase response,42 which is produced in the periphery after central administration of anti-Fas. This is very similar to what occurs with IL-1 that, when injected i.c.v., induces a peripheral acute-phase response,22,43 probably due to centrally mediated induction of peripheral IL-6.21

The fact that central injection of anti-Fas activates the HPAA might imply that hypothalamic neurons are responsive to Fas, ie, express Fas. To our knowledge, there are no studies on the localization of Fas in adult brain, but expression of Fas in the brain of adult mice was reported.44

However, in vitro studies with cells of the central nervous system have shown that Fas is expressed in oligodendroglia, particularly astrocytes, rather than on neurons,45 and similar results were obtained by immunohistochemistry in MS brains.4 It is thus possible that the activation of the HPAA reported in the present paper might be mediated by the activation of the cytokine cascade, as suggested by the induction of IL-6, although induction of serum corticosterone cannot be due only to induction of IL-6 as administration of IL-6 alone does not significantly increase serum corticosterone in our experimental model.14,35

On the other hand, IL-6 is a potent inducer of SAA,14 and it cannot be excluded that it mediates the elevation of SAA observed after anti-Fas injection. The induction of an acute-phase protein by Fas reported here might be important in the observed elevation of acute-phase proteins in experimental autoimmune encephalomyelitis.33,46,47

In conclusion, we have shown that activation of Fas in the central nervous system results in an induction of an acute-phase response and activation of the HPAA similar to those of TNF, previously reported to be mediated by TNFR p55. These actions, particularly elevation of corticosterone and of acute-phase proteins, might counteract pro-inflammatory cytokines and thus have a protective effect in some diseases associated with Fas activation.


   Acknowledgements
 
We are gratefully indebted to Dr. Shigekazu Nagata, Osaka University Medical School, Osaka, Japan, for the gift of anti-FAS MAb Jo2.


   Footnotes
 
Address reprint requests to Dr. Pietro Ghezzi, Laboratory of Neuroimmunology, Istituto di Ricerche Farmacologiche "Mario Negri", via Eritrea 62, 20157 Milano, Italy. E-mail: ghezzi{at}irfmn.mnegri.it

The contribution of L. Aloe is supported by Progetto biotecnologie, Minis-tero dell' Universita' e della Ricerca Scientifica e Tecnologica, Rome, Italy.

Accepted for publication July 24, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Nagata S: Apoptosis by death factor (review). Cell 1997, 88:355-365[Medline]
  2. Bazzoni F, Beutler B: The tumor necrosis factor ligand and receptor family. N Engl J Med 1996, 334:1717-1725[Free Full Text]
  3. Liu C-C, Young LHY, Young JD-E: Lymphocyte-mediated cytolysis and disease. N Engl J Med 1996, 335:1651-1659[Free Full Text]
  4. D'Souza SD, Bonetti B, Balasingam V, Cashman NR, Barker PA, Troutt AB, Raine CS, Antel JP: Multiple sclerosis: fas signaling in oligodendrocyte cell death. J Exp Med 1996, 184:2361-2370[Abstract/Free Full Text]
  5. Becher B, Barker PA, Owens T, Antel JP: CD95-CD95L: can the brain learn from the immune system? Trends Neurosci 1998, 21:114-7[Medline]
  6. Rensing EA, Hess S, Ziegler-Heitbrock HW, Riethmuller G, Engelmann H: Fas/Apo-1 activates nuclear factor kappa B and induces interleukin 6 production. J Inflamm 1995, 45:161-174[Medline]
  7. Sekine C, Yagita H, Kobata T, Hasunuma T, Nishioka K, Okumura K: Fas-mediated stimulation induces IL-8 secretion by rheumatoid arthritis synoviocytes independently of CPP32-mediated apoptosis. Biochem Biophys Res Commun 1996, 228:14-20[Medline]
  8. Tanaka M, Suda T, Yatomi T, Nakamura N, Nagata S: Lethal effect of recombinant human Fas ligand in mice pretreated with Propionibacterium acnes. J Immunol 1997, 158:2303-2309[Abstract]
  9. Rodriguez I, Matsuura K, Ody C, Nagata S, Vassalli P: Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death. J Exp Med 1996, 184:2067-2072[Abstract/Free Full Text]
  10. Chrousos GP: The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995, 332:1351-1362[Free Full Text]
  11. Fantuzzi G, Ghezzi P: Glucocorticoids as cytokine inhibitors: role in neuroendocrine control and therapy of inflammatory diseases. Mediators Inflamm 1993, 2:263-270
  12. Besedovsky H, Del Rey A, Dinarello CA: Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986, 233:652-654[Abstract/Free Full Text]
  13. Mefford IN, Masters CF, Heyes MP, Eskay RL: Cytokine-induced activation of the neuroendocrine stress axis persists in endotoxin-tolerant mice. Brain Res 1991, 557:327-330[Medline]
  14. Benigni F, Fantuzzi G, Sironi M, Sacco S, Pozzi P, Dinarello CA, Sipe JD, Poli V, Cappelletti M, Paonessa G, Panayotatos N, Pennica D, Ghezzi P: Six different cytokines that share gp 130 as a receptor subunit, induce serum amyloid A and potentiate the induction of interleukin-6 and the activation of the hypothalamus-pituitary-adrenal axis by interleukin-1. Blood 1995, 87:1851-1854[Abstract/Free Full Text]
  15. Fantuzzi G, Di Santo E, Sacco S, Benigni F, Ghezzi P: Role of the hypothalamus-pituitary-adrenal axis in the regulation of tumor necrosis factor production in mice: effect of stress and inhibition of endogenous glucocorticoids. J Immunol 1995, 155:3552-3555[Abstract]
  16. Bertini R, Bianchi M, Ghezzi P: Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med 1988, 167:1708-1712[Abstract/Free Full Text]
  17. MacPhee IAM, Antoni FA, Mason DW: Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med 1989, 169:431-445[Abstract/Free Full Text]
  18. Mason D: Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today 1991, 12:57-60[Medline]
  19. Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ, Gold PW, Wilder RL: Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci USA 1989, 86:2374-2378[Abstract/Free Full Text]
  20. Benigni F, Faggioni R, Sironi M, Fantuzzi G, Vandenabeele P, Takahashi N, Sacco S, van Tits LJH, Fiers W, Buurman W, Ghezzi P: Tumor necrosis factor receptor p55 plays a major role in centrally-mediated increases of serum IL-6 and corticosterone after intracerebroventricular injection of TNF. J Immunol 1996, 157:5563-5568[Abstract]
  21. De Simoni MG, Sironi M, De Luigi A, Manfridi A, Mantovani A, Ghezzi P: Intracerebroventricular injection of interleukin 1 induces high circulating levels of interleukin 6. J Exp Med 1990, 171:1773-1778[Abstract/Free Full Text]
  22. Bailey PT, Abeles FB, Hauer EC, Mapes CA: Intracerebroventricular administration of leukocytic endogenous mediator (LEM) in the rat. Proc Soc Exp Biol Med 1976, 153:419-423[Medline]
  23. Blatteis CM: Neuromodulative actions of cytokines. Yale J Biol Med 1990, 63:133-146[Medline]
  24. Nonogaki K, Moser AH, Shigenaga J, Feingold KR, Grunfeld C: ß-Nerve growth factor as a mediator of the acute phase response in vivo. Biochem Biophys Res Commun 1996, 219:956-961[Medline]
  25. Haley TJ, McCormick WG: Pharmacological effects produced by intracerebral injection of drugs in the conscious mice. Br J Pharmacol 1957, 12:12-15[Medline]
  26. Lipton JM, Macaluso A, Hiltz ME, Catania A: Central administration of the peptide {alpha}-MSH inhibits inflammation in the skin. Peptides 1991, 12:795-798[Medline]
  27. Bocchini V, Angeletti PU: The nerve growth factor: purification as a 30,000-molecular weight protein. Proc Natl Acad Sci USA 1969, 64:787-794[Abstract/Free Full Text]
  28. Aloe L: Adrenoalectomy decreases nerve growth factor in young adult rats' hippocampus. Proc Natl Acad Sci USA 1989, 86:5636-5640[Abstract/Free Full Text]
  29. Sironi M, Breviario F, Proserpio P, Biondi A, Vecchi A, Van Damme J, Dejana E, Mantovani A: IL-1 stimulates IL-6 production in endothelial cells. J Immunol 1989, 142:549-553[Abstract]
  30. Vogels MTE, Cantoni L, Carelli M, Sironi M, Ghezzi P, van der Meer JWM: Role of acute-phase proteins in interleukin-1-induced nonspecific resistance to bacterial infections in mice. Animicrob Agents Chemother 1993, 37:2527-2533[Abstract/Free Full Text]
  31. Libert C, Brouckaert P, Fiers W: Protection by {alpha}1-acid glycoprotein against tumor necrosis factor-induced lethality. J Exp Med 1994, 180:1571-1575[Abstract/Free Full Text]
  32. Xia D, Samols D: Transgenic mice expressing rabbit C-reactive protein are resistant to endotoxemia. Proc Natl Acad Sci USA 1997, 94:2575-2580[Abstract/Free Full Text]
  33. Hunter N, Weston KM, Bowern NA: Suppression of experimental allergic encephalomyelitis by alpha 2-macroglobulin. Immunology 1991, 73:58-63[Medline]
  34. Aderka D, Le J, Vilcek J: IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice. J Immunol 1989, 143:3517-3523[Abstract]
  35. Di Santo E, Alonzi T, Poli V, Fattori E, Toniatti C, Sironi M, Ricciardi-Castagnoli P, Ghezzi P: Differential effects of IL-6 on systemic and central production of TNF. Cytokine 1997, 9:300-306[Medline]
  36. Fattori E, Cappelletti M, Costa P, Sellitto C, Cantoni L, Carelli M, Faggioni R, Fantuzzi G, Ghezzi P, Poli V: Defective inflammatory response in IL-6 deficient mice. J Exp Med 1994, 180:1243-1250[Abstract/Free Full Text]
  37. Nagata S, Golstein P: The Fas death factor. Science 1995, 267:1449-1456[Abstract/Free Full Text]
  38. Malinin NL, Boldin MP, Kovalenko AV, Wallach D: MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 1997, 385:540-544[Medline]
  39. Carter BD, Kaltschmidt C, Kaltschmidt B, Offenhauser N, Bohm-Matthaei R, Baeuerle PA, Barde YA: Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 1996, 272:542-545[Abstract]
  40. Korner M, Tarantino N, Pleskoff O, Lee LM, Debre P: Activation of nuclear factor kappa B in human neuroblastoma cell lines. J Neurochem 1994, 62:1716-1726[Medline]
  41. Wood JN: Regulation of NF-kappa B activity in rat dorsal root ganglia and PC12 cells by tumour necrosis factor and nerve growth factor. Neurosci Lett 1995, 192:41-44[Medline]
  42. Heinrich PC, Castell JV, Andus T: Interleukin 6 and the acute-phase response. Biochem J 1990, 265:621-636[Medline]
  43. Turchik JB, Bornstein DL: Role of the central nervous system in acute-phase responses to leukocytic pyrogen. Infect Immun 1980, 30:439-444[Abstract/Free Full Text]
  44. French LE, Hahne M, Viard I, Radlgruber G, Zanone R, Becker K, Muller C, Tschopp J: Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. J Cell Biol 1996, 133:335-343[Abstract/Free Full Text]
  45. Becher B, D'Souza SD, Troutt AB, Antel JP: Fas expression on human fetal astrocytes without susceptibility to fas-mediated cytotoxicity. Neuroscience 1998, 84:627-34[Medline]
  46. Banati RB, Gehrmann J, Lannes-Vieira J, Wekerle H, Kreutzberg GW: Inflammatory reaction in experimental autoimmune encephalomyelitis (EAE) is accompanied by a microglial expression of the beta A4-amyloid precursor protein (APP). Glia 1995, 14:209-215[Medline]
  47. Du Clos TW, Mold C, Paterson PY, Alroy J, Gewurz H: Localization of C-reactive protein in inflammatory lesions of experimental allergic encephalomyelitis. Clin Exp Immunol 1981, 43:565-573[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Benigni, F.
Right arrow Articles by Ghezzi, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Benigni, F.
Right arrow Articles by Ghezzi, P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS