Heumann, R.

Lindholm, D.

Meyer, Michael

Thoenen, Hans

English

Universität München: Elektronischen Publikationen

Interleukin-l regulates synthesis of 
nerve growth factor in 
non-neuronal cells of rat sciatic nerve 
Dan Lindholm, Rolf Heumano, Michael Meyer 
& Hans Thoeneo 
Department of Neurochcmistry, Max-Planck- lnstilUle for Psychiatry, 
D-8033 ptanegg-Martinsried, FRG 
ne Schwano « 11s Bnd fibroblast-lIke cells oe tbe iatBet seiatie 
Bene oe adult rats syathalze very little nerve growth (actoT (NGF) 
(nr. I). After IHion, bOll"cver, tben Is a dramatk increase in tbe 
.mounts oe botb NGF-mRNA and NGF proteia syothesized by 
lhe seistle nOD-neuronal cells!,l, TbilJ locallncrease in NGF sr.-
thesis partlally replaces the loterrupted NGF supply (rom the 
periphery 10 the NGF-respoDsive 5eOSOI')' u d sympathetlc neurons, 
wbose axODS ruD "ithln the sclatk nene!. Macrophages, Down 
10 lovade tbe slte of Mn" lesion during wallerian dqeoeratlooJ.· , 
are import.nt in the regulation oe NGF synthesiS'. Here we demon-
stnte ebat tbe efl'ect of maeropbage5 on NGF-mRNA levels In 
cultured explants of sei.eie oerve C&n be mimieked by condltioned 
media of actl"ated macrophages, aad that iDterleukio-t Is the 
responsible agent. 
'00 a , 
~ 
300 ! a 
J~_! 
, , 
" 200 • I z 
I • '00 ,
" ; • 0 z 0 , 
0 , " " T;me '" h , 
~ "'" ., 
~ i\ --" • 300 • / , ! \ , " ' ' 200 ......... i \ I • " ~~ z • '00 I . I , " " I 0 " • " z 0 , , , , , 
0 , " " 03 " 20 30 Time I h I Il- I I Uml -1 
Flg_ I a, Changes in NGF_mRNA levels of ral sciaüc nerve 
segmenu by condi tioned media of aClivated rat macrophages. b, 
TIme course of induetion by IL-Iß. Human recombinant IL-Iß 
(30 U mI- I) of spedfic aetivily 4 )( Hf U I1g- 1 protein was used. 
The dashed line shows the eHeet of re ·addition of IL-Iß to cuhures 
incubated 12 h with the protein. C, IL-Iß dose-response curve for 
NGF-mRNA induetion. The incubation was for Ihree hours and 
averages of two determinalions at each concentration are given. 
Melhods. Seiatic nerve segments (3 cm) of adult Wistar rats were 
culturc:d in I ml Dulbeeco's modi lied Eagle's medium supple-
mented with 10% feta l calfserum. After th ree days culturc, medium 
conditioncd by either rat peritoneal macrophages or human recom-
binant IL- Iß was added. Rat periloncal macrophagc:s were purified 
by allachment to plastic, and activated with lipopolysaccharide 
(LPS) (Sigma) for 20 h (10 I-I-g ml- L). Media eonditioned by the 
adherent cells with more than 95% macrophages, as evalualed by 
the speeific anlibody EDI (ref. 17), wert eolleeted and added to 
the nerve explant cultures. NG F-mRNA was determined by a quan-
titat ive Northern blot procedure, using a calibration standard (0.92 
ki lobases (kb» for NGF-mRNA (rtf. 16). The recovery o f RNA 
was estimated using a shorter NGF-mRNA transcript (0 .5 1 kb), 
whieh was added 10 the tissue sampies before RNA euraetion'6. 
The aUloradiograms were quantified 0 0 a scaoning densitometer 
for the amouot of NGF-mRNA preseot. Valucs are expressed as 
fg per mg wet weight of ti ssue, and they represeot mean "'s.d. of 
three or more separate detenninalion$. The open eirdes represent 
the conlrol values of n~rve segments incubated fo r 24 h. 
In previous experimenls we have shown that although the 
lesion-mcdiated incrcase in NGF-m RNA is biphasic in vivo L, 
in cultures of rat sciatic nerve thefe was only a rapid a nd t ransient 
increase in NGF-mRNA, which was not fo llowed by the chronic 
rise observed in vivo ~. The addition o f activat~d macrophages 
to the cul ture system resulted in increase of sciatic NGF-mRNA 
comparable to that obse rved in vivo5• To decide wheth er these 
effects result from cell- cell conlact or are mediated by a humoral 
faclor, we prepared m~dia conditioned by activated rat 
macrophages. Figure I shows that rat sciatic nerve segments 
cultured for three days contained only relatively low a mounts 
of NGF-mRNA which were markedly (I I -fold) enhanced when 
the cultur~s were supplemented b y macrophage-con d ilioned 
m~dia , to reach a stabl~ m aximum after three ho urs. Of the 
many biologically aetive m oleeules synth~sized by activat~d 
macro phages'. prostagiandin El , a nd acidic a nd basic fib ro blast 
growth factor ( FGF) did not aITeet the amount of NGF-mR NA 
T.bJe I Effeet of different agents on rat $ciatic nerve NGF-mRNA 
transcription 
Controls 
+ PGE, 
+acidic FGF 
+basic FGF 
+PDGF 
+TNF 
Sciatic NGF_mRNA 
(rg per mg tissue) 
34.5 
47.2 
28.0 
29.0 
71.3 
75.2 
Agents were added to sciatic nerve segments after culture for three 
days. Afler incubation for three hours, sciatic NGF-mRNA was quanti-
tated u described in Fig. I legend. Prostagiandin E1 (Sigma) was uscd 
at a final concentration of 5 ~M (ref. 18); acidic and basic FGF (a gift 
rrom Dr Sensenbrenner'9) were at a concentration of 5 ng mi - I. PDGF 
(Speywood, UK) was used at a concentration of 3 U ml- ' (ref. 20). 
Human TNF-a (eacheetin; Amgen. Amersham) was used at a final 
concentration of 1,000 U mI- I (ref. 2 \ ). These concentrations are com-
parable to Ihose known to produce a maximal effect. Values reprcsent 
the average of (WO or more separate deterrninations. 
produced (Table I ). Tumour neerosis factor (TNF) and platelet-
derived growth factor (POGF), whieh are major eonstituents of 
maerophage-eonditioned media7 , doubled the amounl of NGF-
mRNA presenl. But the addition of recombinant human inter-
leukin-Iß (IL.- Iß ) (ref. 8) resulted in a 14-fold inerease in NGF-
mRNA (Fig.lb). The effect of IL-I ,8 was diseemible at a con-
centration of 1 U mi- I and was maximal at about 10 U mi- I. No 
difference was seen between the effeets of recombinant IL- l a 
and IL.-l,8 whieh are both produeed by activated macrophages9 , 
supporting the view that these structurally different molecules 
(the homology between human and murine IL-Ia and IL.-I ß is 
only 30% 10 _12 ) have similar biological activities. Tbe eflects of 
human IL-I and rat macrophage-eonditioned medium on NGF-
mRNA are similar, both with respeci 10 the extenl and the 
time-course of the increase. Re-addition of IL-I ß after 12 hOU TS 
resulted in a repeat inerease in NG F-mRNA tOlhe level observed 
after the first addition, indicaling that Ihe protein was either not 
stable, or was degraded by the sciatic explants. 
Because antibodies to rat IL-I were not available, we used 
conditioned media of human macrophages, which aHected the 
amounts ofrat sciatic nerve NGF-mRNA produced to the same 
extent as the rat medium. The inerease in NGF-mRNA observed 
after addition of recombinant IL-I and human macrophage-
derived medium could bolh be inhibited to the same extent by 
specific polyclonal anlibodies to human IL-I (Fig.2). Thus, 
most, if not all , of the aelivity of the human macrophage-
conditioned medium is due 10 IL-t. It is probable Ihat the same 
is true for the eonditioned medium of rat maerophages, allhough 
direct proof is not yel possible due to the unavailability of 
antibodies to rat IL· I and 10 the poor interspecies immunological 
cross_reactivityll. Our interpretation is supported by the associ-
at ion ofthe activity ofthe rat-conditioned medium with fraetions 
of relative moleeular mass (M,) between 10,000-20,000 (10-
20K) (data not shown). 
These results could explain the in vivo and the in vitro dis-
crepancys; in virf"O, macrophages must be added to simulate the 
ehronie inerease in NGF-mRNA whieh occurs after lesion in 
vivo, and which remains high for more than two weeks '·'. Fol -
lowing a peripheral nerve injury, maerophages invade the si te 
of lesion1 •4 to stimulate eoncomitant increase in NGF-mRNA 
levels'. These observations combined witb OUTS indicale that 
macrophages are responsible for the persistent increase in NGF 
in the injured nerve in vivo. Note that macrophages themselves 
synthesize very little NGF (ref. 5), therefore their eontribution 
"Xl 
'" 300 
< z 200 • ,
" ~ z 
o .L.L...Ll-
Con lrOI H-l Medium 
Fig. 2 Effcct of macrophage_conditioned medium on sciatic 
NG F-mRNA; blockade by antibodies to 1L- 1. Condilioned media 
derived from LPS·aclivated human peritoneat macrophagcs were 
diluted 1 10 20 and used in the ral nerve explant cullures (see 
Fig. I ). Apart of the medium was prctreatcd with rabbit antibodies 
raised again$! human fL-l before adding it 10 the culturc system. 
As a control 30 U of human recombinant lL·\ was treated similarly 
and then added to ellplant cultures. The antibodics used werc 
polyvalent (Gen:.:yme, Boston). Following incubation for Ihree 
hours, the amounts of sciatic NGF-mRNA present were deter-
mincd as described in Fig. I legend. The open bars show the results 
of incubating the nerve pieees with IL-I or with the buman 
macrophage-conditioned medium; tbe hatehed bars represenl 
resulls after prelrcalmcnl oflhe medium or of 11..-\ Wilh the specifie 
antibodies. Thc valu ~s represent mean ±s.d. of three independent 
delerrninations. 
to the amount of NGF present is indirect and mediated mainly 
by IL-1. 
Macrophages and the IL.-l they release could also be impor-
tant in the regulation of NGF synthesis during normal develop-
ment; the amount of NGF~mRNA in the sciatic nerve of 
newbom ra ts is comparable to that in lesioned adult nerves ' , 
and decreases to adult values by the thi rd postnatal week~, by 
whieh time the high density of macrophages in the newbom rat 
sciatic nerve has also decreased to the low intaet adult nerve 
levels·. Intereslingly, TL-I aetivity has also been detected in the 
central nervous system following brain injuryl\ but cellular site 
of synthesis has not yel been established ' l •1S• 
We thank Dr A. Shaw (Biogen) and A. Gronenbom (Martins-
ried) for a gift ofhuman recombinant IL-l. We are also grateful 
to Or M. Blumenstein for help with obtaining human 
macrophages, 10 Elfi Grossmann for typing the manuscripl, and 
10 Ors D . Edgar and Y.-A. Barde for eri tically reviewing the 
manuseript. O.L. is a recipient of a rellowship from EMBO. 
I. Humann. R.. )(orsckinl. S .• 9ondlla ..... C . '" Thotnen. H. J ... U ßi<>I. 184. l62l_ 1611 (1987). 
2. 8andtJa ..... C. E.. Heu",,"nn. R.. Schwab. M. E.,t. n.o..n.-n. H. 1:""1>1801. " 891-899 (l9J"1). 
3. Ptrry. v. H~ 8",-.. M. C. '" Ciatdon. S. J. Dp. Mn 166. 1213_1221 (1987). 
.. Stall. G. &. Miille,. H_ W. N ... TtJMl. Ü'l 72, 233_238 (19M). 
S. Hellmann, R. J. C1Cp. Bio{ 1.U. Ul-lSO (1917). 
6. HOIh.n. C. F .• Mu .... y. H. W. '" Coha. Z " . Ncw Enrl J. Mn JO), 622-626 ( 19SO). 
7. ShimQkado. )(. CI aI. Ce/I 43, m-2U (l98S). 
8. Winp<I<I. P.~' ~t F.~ •. J. 8""'""""- t60. 49 1~7 (19116). 
9. Opptnh<im. J. J .. Ko ... ",. Fe J .• M'I>~.hi .... K_,t. Du"''''. S. K. I", .. ~ ... r"., 7, .S·S6 
(1986). 
10. M>rch. C. J. CI.1 N.", .. 3 15, 641 _M 11191$). 
11 . l.o"'.dko. P. T.~,.t N., ... 111. 458_~1 ( t984 ). 
12. "urnn. P. E. e 'nl Proc: "", ... .4,0<1.sn: U.$.A " , 7"907_791 1 ( 1984). 
lJ. Giuli.n, 0 ., 8.k<f. T . J .• Sruh. 1.-<:. N. '" Lacllman. I.. B. J. «p. MN. 164, 5~604 ( 1986). 
14. Giulian. D . .t Lachman. I.. 11. 5(;""u ua, 491_499 (1915). 
15. Fonun •• A., Kri ... n .. n . F .• Dubo. R .• Gorn ... 1) ... W<!>e,. !;. J. Im","" 12', ;'411 _2419 
(1982). 
16. Heum.nn. R_ '" Tb.,.""n. 11. 1. bi<>I. a.. .... UI , 9;>.46..92.9 ( t9116). 
17. Dijh'nI. C. D .• 001'1'. E. A .• Joli.,. P. '" Krul. G . l,"m~ooIoKy 54. 589- $')'9 ( 19M). 
18. lI,and"e;n. S. R. J. b<ol CI>tnr. UI, Ul4-U12 (t986). 
19. "'"man. B .• ~unl,",. G .• Weibe!. M. '" Seß<enh,enner. M. N ... fMri. utt 61, 175_180 
( 19116). 
10. c.,.."ßbe,.. M. F. . .t 7~~. F.. B. N~,",e Jll, oIJl_~lg (198<1). 
21 . Bevil>"'!u>. M. P. ".L Proc: ..,Ur. A<a<I. S</. U.S. A. l), ~~l3 -4517 ( 19&6). 


Interleukin-l regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve

Open Access LMU

Interleukin-l regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve Dan Lindholm, Rolf Heumano, Michael Meyer & Hans Thoeneo Department of Neurochcmistry, Max-Planck- lnstilUle for Psychiatry, D-8033 ptanegg-Martinsried, FRG ne Schwano « 11s Bnd fibroblast-lIke cells oe tbe iatBet seiatie Bene oe adult rats syathalze very little nerve growth (actoT (NGF) (nr. I). After IHion, bOll"cver, tben Is a dramatk increase in tbe .mounts oe botb NGF-mRNA and NGF proteia syothesized by lhe seistle nOD-neuronal cells!,l, TbilJ locallncrease in NGF sr.-thesis partlally replaces the loterrupted NGF supply (rom the periphery 10 the NGF-respoDsive 5eOSOI')' u d sympathetlc neurons, wbose axODS ruD "ithln the sclatk nene!. Macrophages, Down 10 lovade tbe slte of Mn" lesion during wallerian dqeoeratlooJ.· , are import.nt in the regulation oe NGF synthesiS'. Here we demon-stnte ebat tbe efl'ect of maeropbage5 on NGF-mRNA levels In cultured explants of sei.eie oerve C&n be mimieked by condltioned media of actl"ated macrophages, aad that iDterleukio-t Is the responsible agent. '00 a , ~ 300 ! a J~_! , , " 200 • I z I • '00 ," ; • 0 z 0 , 0 , " " T;me '" h , ~ "'" ., ~ i\ --" • 300 • / , ! \ , " ' ' 200 ......... i \ I • " ~~ z • '00 I . I , " " I 0 " • " z 0 , , , , , 0 , " " 03 " 20 30 Time I h I Il- I I Uml -1 Flg_ I a, Changes in NGF_mRNA levels of ral sciaüc nerve segmenu by condi tioned media of aClivated rat macrophages. b, TIme course of induetion by IL-Iß. Human recombinant IL-Iß (30 U mI- I) of spedfic aetivily 4 )( Hf U I1g- 1 protein was used. The dashed line shows the eHeet of re ·addition of IL-Iß to cuhures incubated 12 h with the protein. C, IL-Iß dose-response curve for NGF-mRNA induetion. The incubation was for Ihree hours and averages of two determinalions at each concentration are given. Melhods. Seiatic nerve segments (3 cm) of adult Wistar rats were culturc:d in I ml Dulbeeco's modi lied Eagle's medium supple-mented with 10% feta l calfserum. After th ree days culturc, medium conditioncd by either rat peritoneal macrophages or human recom-binant IL- Iß was added. Rat periloncal macrophagc:s were purified by allachment to plastic, and activated with lipopolysaccharide (LPS) (Sigma) for 20 h (10 I-I-g ml- L). Media eonditioned by the adherent cells with more than 95% macrophages, as evalualed by the speeific anlibody EDI (ref. 17), wert eolleeted and added to the nerve explant cultures. NG F-mRNA was determined by a quan-titat ive Northern blot procedure, using a calibration standard (0.92 ki lobases (kb» for NGF-mRNA (rtf. 16). The recovery o f RNA was estimated using a shorter NGF-mRNA transcript (0 .5 1 kb), whieh was added 10 the tissue sampies before RNA euraetion'6. The aUloradiograms were quantified 0 0 a scaoning densitometer for the amouot of NGF-mRNA preseot. Valucs are expressed as fg per mg wet weight of ti ssue, and they represeot mean "'s.d. of three or more separate detenninalion$. The open eirdes represent the conlrol values of n~rve segments incubated fo r 24 h. In previous experimenls we have shown that although the lesion-mcdiated incrcase in NGF-m RNA is biphasic in vivo L, in cultures of rat sciatic nerve thefe was only a rapid a nd t ransient increase in NGF-mRNA, which was not fo llowed by the chronic rise observed in vivo ~. The addition o f activat~d macrophages to the cul ture system resulted in increase of sciatic NGF-mRNA comparable to that obse rved in vivo5• To decide wheth er these effects result from cell- cell conlact or are mediated by a humoral faclor, we prepared m~dia conditioned by activated rat macrophages. Figure I shows that rat sciatic nerve segments cultured for three days contained only relatively low a mounts of NGF-mRNA which were markedly (I I -fold) enhanced when the cultur~s were supplemented b y macrophage-con d ilioned m~dia , to reach a stabl~ m aximum after three ho urs. Of the many biologically aetive m oleeules synth~sized by activat~d macro phages'. prostagiandin El , a nd acidic a nd basic fib ro blast growth factor ( FGF) did not aITeet the amount of NGF-mR NA T.bJe I Effeet of different agents on rat $ciatic nerve NGF-mRNA transcription Controls + PGE, +acidic FGF +basic FGF +PDGF +TNF Sciatic NGF_mRNA (rg per mg tissue) 34.5 47.2 28.0 29.0 71.3 75.2 Agents were added to sciatic nerve segments after culture for three days. Afler incubation for three hours, sciatic NGF-mRNA was quanti-tated u described in Fig. I legend. Prostagiandin E1 (Sigma) was uscd at a final concentration of 5 ~M (ref. 18); acidic and basic FGF (a gift rrom Dr Sensenbrenner'9) were at a concentration of 5 ng mi - I. PDGF (Speywood, UK) was used at a concentration of 3 U ml- ' (ref. 20). Human TNF-a (eacheetin; Amgen. Amersham) was used at a final concentration of 1,000 U mI- I (ref. 2 \ ). These concentrations are com-parable to Ihose known to produce a maximal effect. Values reprcsent the average of (WO or more separate deterrninations. produced (Table I ). Tumour neerosis factor (TNF) and platelet-derived growth factor (POGF), whieh are major eonstituents of maerophage-eonditioned media7 , doubled the amounl of NGF-mRNA presenl. But the addition of recombinant human inter-leukin-Iß (IL.- Iß ) (ref. 8) resulted in a 14-fold inerease in NGF-mRNA (Fig.lb). The effect of IL-I ,8 was diseemible at a con-centration of 1 U mi- I and was maximal at about 10 U mi- I. No difference was seen between the effeets of recombinant IL- l a and IL.-l,8 whieh are both produeed by activated macrophages9 , supporting the view that these structurally different molecules (the homology between human and murine IL-Ia and IL.-I ß is only 30% 10 _12 ) have similar biological activities. Tbe eflects of human IL-I and rat macrophage-eonditioned medium on NGF-mRNA are similar, both with respeci 10 the extenl and the time-course of the increase. Re-addition of IL-I ß after 12 hOU TS resulted in a repeat inerease in NG F-mRNA tOlhe level observed after the first addition, indicaling that Ihe protein was either not stable, or was degraded by the sciatic explants. Because antibodies to rat IL-I were not available, we used conditioned media of human macrophages, which aHected the amounts ofrat sciatic nerve NGF-mRNA produced to the same extent as the rat medium. The inerease in NGF-mRNA observed after addition of recombinant IL-I and human macrophage-derived medium could bolh be inhibited to the same extent by specific polyclonal anlibodies to human IL-I (Fig.2). Thus, most, if not all , of the aelivity of the human macrophage-conditioned medium is due 10 IL-t. It is probable Ihat the same is true for the eonditioned medium of rat maerophages, allhough direct proof is not yel possible due to the unavailability of antibodies to rat IL· I and 10 the poor interspecies immunological cross_reactivityll. Our interpretation is supported by the associ-at ion ofthe activity ofthe rat-conditioned medium with fraetions of relative moleeular mass (M,) between 10,000-20,000 (10-20K) (data not shown). These results could explain the in vivo and the in vitro dis-crepancys; in virf"O, macrophages must be added to simulate the ehronie inerease in NGF-mRNA whieh occurs after lesion in vivo, and which remains high for more than two weeks '·'. Fol -lowing a peripheral nerve injury, maerophages invade the si te of lesion1 •4 to stimulate eoncomitant increase in NGF-mRNA levels'. These observations combined witb OUTS indicale that macrophages are responsible for the persistent increase in NGF in the injured nerve in vivo. Note that macrophages themselves synthesize very little NGF (ref. 5), therefore their eontribution "Xl '" 300 < z 200 • ," ~ z o .L.L...Ll-Con lrOI H-l Medium Fig. 2 Effcct of macrophage_conditioned medium on sciatic NG F-mRNA; blockade by antibodies to 1L- 1. Condilioned media derived from LPS·aclivated human peritoneat macrophagcs were diluted 1 10 20 and used in the ral nerve explant cullures (see Fig. I ). Apart of the medium was prctreatcd with rabbit antibodies raised again$! human fL-l before adding it 10 the culturc system. As a control 30 U of human recombinant lL·\ was treated similarly and then added to ellplant cultures. The antibodics used werc polyvalent (Gen:.:yme, Boston). Following incubation for Ihree hours, the amounts of sciatic NGF-mRNA present were deter-mincd as described in Fig. I legend. The open bars show the results of incubating the nerve pieees with IL-I or with the buman macrophage-conditioned medium; tbe hatehed bars represenl resulls after prelrcalmcnl oflhe medium or of 11..-\ Wilh the specifie antibodies. Thc valu ~s represent mean ±s.d. of three independent delerrninations. to the amount of NGF present is indirect and mediated mainly by IL-1. Macrophages and the IL.-l they release could also be impor-tant in the regulation of NGF synthesis during normal develop-ment; the amount of NGF~mRNA in the sciatic nerve of newbom ra ts is comparable to that in lesioned adult nerves ' , and decreases to adult values by the thi rd postnatal week~, by whieh time the high density of macrophages in the newbom rat sciatic nerve has also decreased to the low intaet adult nerve levels·. Intereslingly, TL-I aetivity has also been detected in the central nervous system following brain injuryl\ but cellular site of synthesis has not yel been established ' l •1S• We thank Dr A. Shaw (Biogen) and A. Gronenbom (Martins-ried) for a gift ofhuman recombinant IL-l. We are also grateful to Or M. Blumenstein for help with obtaining human macrophages, 10 Elfi Grossmann for typing the manuscripl, and 10 Ors D . Edgar and Y.-A. Barde for eri tically reviewing the manuseript. O.L. is a recipient of a rellowship from EMBO. I. Humann. R.. )(orsckinl. S .• 9ondlla ..... C . '" Thotnen. H. J ... U ßi<>I. 184. l62l_ 1611 (1987). 2. 8andtJa ..... C. E.. Heu",,"nn. R.. Schwab. M. E.,t. n.o..n.-n. H. 1:""1>1801. " 891-899 (l9J"1). 3. Ptrry. v. H~ 8",-.. M. C. '" Ciatdon. S. J. Dp. Mn 166. 1213_1221 (1987). .. Stall. G. &. Miille,. H_ W. N ... TtJMl. Ü'l 72, 233_238 (19M). S. Hellmann, R. J. C1Cp. Bio{ 1.U. Ul-lSO (1917). 6. HOIh.n. C. F .• Mu .... y. H. W. '" Coha. Z " . Ncw Enrl J. Mn JO), 622-626 ( 19SO). 7. ShimQkado. )(. CI aI. Ce/I 43, m-2U (l98S). 8. Winp<I<I. P.~' ~t F.~ •. J. 8""'""""- t60. 49 1~7 (19116). 9. Opptnh<im. J. J .. Ko ... ",. Fe J .• M'I>~.hi .... K_,t. Du"''''. S. K. I", .. ~ ... r"., 7, .S·S6 (1986). 10. M>rch. C. J. CI.1 N.", .. 3 15, 641 _M 11191$). 11 . l.o"'.dko. P. T.~,.t N., ... 111. 458_~1 ( t984 ). 12. "urnn. P. E. e 'nl Proc: "", ... .4,0<1.sn: U.$.A " , 7"907_791 1 ( 1984). lJ. Giuli.n, 0 ., 8.k<f. T . J .• Sruh. 1.-<:. N. '" Lacllman. I.. B. J. «p. MN. 164, 5~604 ( 1986). 14. Giulian. D . .t Lachman. I.. 11. 5(;""u ua, 491_499 (1915). 15. Fonun •• A., Kri ... n .. n . F .• Dubo. R .• Gorn ... 1) ... W<!>e,. !;. J. Im","" 12', ;'411 _2419 (1982). 16. Heum.nn. R_ '" Tb.,.""n. 11. 1. bi<>I. a.. .... UI , 9;>.46..92.9 ( t9116). 17. Dijh'nI. C. D .• 001'1'. E. A .• Joli.,. P. '" Krul. G . l,"m~ooIoKy 54. 589- $')'9 ( 19M). 18. lI,and"e;n. S. R. J. b<ol CI>tnr. UI, Ul4-U12 (t986). 19. "'"man. B .• ~unl,",. G .• Weibe!. M. '" Seß<enh,enner. M. N ... fMri. utt 61, 175_180 ( 19116). 10. c.,.."ßbe,.. M. F. . .t 7~~. F.. B. N~,",e Jll, oIJl_~lg (198<1). 21 . Bevil>"'!u>. M. P. ".L Proc: ..,Ur. A<a<I. S</. U.S. A. l), ~~l3 -4517 ( 19&6). 

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Interleukin-l regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve

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