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HSP  !+ "#$%+ &#'(+Heat Shock Protein (HSP) Induced by
Mild Hyperthermia Supports Your Health
Youko H. ITOH+, Yoshiaki YAMADA+ and Nobuaki HONDA+

Abstract
We consist of 0* trillion cells that contain a large amount of various proteins. Mostof the components of our body are proteins excluding water. We receive various stresses,
namely, some proteins in our cells receive injuries and they cause the structural abnormality, and then the cellular functions cause disorders.
Heat shock proteins (HSPs) were induced by various environmental stresses including heat stress. Especially, HSP 1* has been studied by many researchers. HSP 1* works
to repair partially injured proteins and facilitate the degradation of irreversible injured
proteins, then protects the cells. HSP 1* also participates in the synthesis, translocation,and degradation of proteins as a molecular chaperone.
We established a mild hyperthermia therapy that was easy and safety method for
induction of HSP. Mild hyperthermia is a therapy utilizing the physiological functions of
HSP 1* (cyteprotective e#ects, immunoenhancing e#ects and molecular chaperone) induced by heat stress for various diseases including cancer and health maintenance. HSP 1*
induced by mild hyperthermia enhances immune activity of NK cells and dendritic cells.
Furthermore, HSP 1* acts as cancer vaccine to complex with cancer antigens.
HSP 1* is a useful and attractive protein that can be easily increased even oneself
when it is necessary.
Key words : Heat shock protein, HSP, Mild hyperthermia, Stress protective protein,
Molecular chaperone

+

380



 .2*῍++3/   ,+ + Department
of Urology, Aichi Medical University School of Medicine, Nagakute-cho ,+, Aichi-gun, Aichi .2*῍++3/, Japan.

 0* ' ,*+*





 HSP ( )! 0* *+,-.! /011)23456 789:;"<=5! (  >?>@ABCD 4EF )! ( G+9:
ABCD0HIJKFL! /M NOL! /PQ! +ABRS.T L
.UF ;"V !
 HSP )! >?>)W ῌXYῌZ[R\]\>?>^<=5+^RS! >?>^<=5ABRS9:_
L! _L`S49:)abU8+>?>,-=54" \!
HSP )! 9:c1ῌdῌa Ve^fgh L5454" HSP)i,- \;8e ej >?>j  5k.! bX^l
L=,.mRS5`nfo ;"( )! plqQ^! ,rst;u >?>^< HSP  ;vwx
y! z"L" vwxy! )!
>?>^<=5RS HSP e{#>?>j{#! $| }{#! fgh{# %#L! ~ 
!! ^&"5! ;" vwxy! ;)! y^< $| }@
' y{#)l <.! RS HSP ^< NK +X+ }! ~{#8~$|^l(L54"/L5)J^*+F ^! HSP )vwxy^<=5! ,-^  G;u^yRF l.;"  x:

! HSP! vwxy! >?>j! fgh+   ) .0*ῌ-11 /! Y0 S >) 12ῌ!3 L
5 # $ 4#5 L54" V ;! ( ) 1@>?>,-  Gej{#=5k.!

-6U + 54" ( z"Lvwxy! )\R^ # y   >?>$  #y$E3#45! (G+^RSej{# >?>j! $| }{#! fgh{#8
e{#%#L54" F )^74 ¡,-S54! /8F/;" 89:;)! F % HSP& ^r45¢£U",  ( )! ;J ¤<AB^R-RS54! kk¥¦§ABle`54" FS)(   G¨3 ej{#  5k.! ;J¤<AB,-jRS5
4,-;" = ©! ( eª«^)R\]\+i@¬w>>­L54! FS-®¯^?L$|°jL! 6 78®¯UF )4" \! ±²L5L5l! ³´µ°XRS³)µ\.¶U" <=5! @A±²;S©! BC;TDL5
L\EF )4" .F ;! F<E^( )  GjUej{# 54"/S;)>?>^?L5)! ( )8<Eej{#=54;·E,",+    ( )! ¸¹>?> /º@£»EF! Z[>?> ¹¸;r`4! ¼½EF
381

               !

"#$ %&' () * +,,- .$/0123
45#$%&'6'*

07&$089:;%<=>1?@;AB2C

9 Heat Shock Protein : HSP  89:;DE$- 
-+  HSP  HSP 

HSP +1?FG?FHI JKLM  DNOP$%QDRP$89:;Q
+30,  Ritossa (S5TU& V 1?FG?FHIW()  X YZ([

$E'\$/(]# HSP <U&$%Q  W()ῌ^ ῌ_ (S5U& 6',,- .5#$%Q<'6Q`a +33. ; Fedder and Ho#man, +333  89:; Q)bc&$Sd(5 
!Z HSP Q= HSP D+ /*῍ )"#e<E$%Q6' HSP +f $g

6'/ .$h %ijῌklmnjS`)U'(o(&/089:;Q#g$ ] HSP (+'(S` HSP +**, HSP 3*, HSP 1*, HSP 0*, HSP .1, HSP .*, HSP ,1
(7f)<TU&#$< *+D+p)(7qrU&#$' 1*,***  HSP 1*
Burdon et al., +32, ; Welch and Feramicso, +32. (s#tu-,  HSP 

* -vww+ 0*῍ <xDE` y((#<89:;DE$ * -+ ,<89:;6'Dz]` -. / 01 {2 |5#$vw89:; 3k}3#k~

B9  ^

A19   C99

9&&4z 4s589:; 689:;DE$ 4z7 8d89:;f)+ +* 9fWE$Q&#$  * -+ 0* :Y;6'<]`Y;7+%&' 89:;Dhz5#$
S5 * < !"$Qd%Q+ Y;< !"$%QDE` Y;7Dhz5#$89:;< !" 89:;v= 5<
U& Y;<U&`>   #\$? QE'&$
%D @P$< 089:;DE$ HSP DE$ E$AB+,,-DCP$0v<4z HSP <U&$

HSP +D !"v= ]%89:; C  CD589:;+ Y;(
P$ Lorimer, +331

6 <E`() z7 CD589:;<(7 EP$+ Y;]7QV( ?¡¢($h  Y;  £¤>1 ¥7--  HSP  HSP +#F¦(+1§ B9 G ¨#©Hª<«¬­¥®¯>P$¦

IzJ5|K°g$L©Hª%Q d : ±JgM

Q Y;ND²M³´#$ Feder and Ho#man, +333Pµ + 89:;w¦(+ ¶·>3D mRNA ¸@¹>G(º#£»¼<½
382

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! - AB

KG)H! JAB)> 0I2345LM0 N,-O?'?P! AB+@ῌE ῌ N ABQR)S'T 0I1" U<=)! HSP HABQR)>  0I!   .H.1! VWXY-Z[KI1'! \-]^_`I1"AB',-G a

G! bcG! HSP d) )KI'

" HSP  e,f)H .";ghi8je;kl) e,fU ;."-. 

 HSPm) KI! n;oU Hpq;3! m) KIrst'c?U Huvw! x.)y U ;" z;i8je)<3,- HSP H
rsc !{0! U )<3"|#}I$(~%?" mOPH!
&') w) ?U H01; hI}(O})K3
01! rs0z;b ?H u)uH* 0Id! + Y-".  !
HSP H! ! +! #! ,ῌ}! -.P/0ῌ

Table + Heat Shock Protein (HSP 1*) is induced bymild hyperthermia.

! 1`! ! +! 12 P¡¢P3 )<3,-Wv-I1" s £;! 4;pd HSP ,-U ! J0I! 4;i8jeH¤¥;5¦)§;.U uv!
s

H HSP 0I! i8je¨60 ©7! +332! ,**, ; ©
7v! ,**3"
 4

ª

Z! «¬)H­a  .-# ®¯)e0I°8,f­4

±?" s 4H! .*$.,#

Table ,

Physiologic functions of HSP 1*.

i8j9;¥we0! a)
4 

HSP   ,f HSP

R%²:;:0! O³´
%ῌcP)6Ii8je HSP  ; Table +"i8je;H! e)<"|' µ! <4¶=/·;¸j8
6¹ºR»<¼e)<3,-HSP >?R0²: Table , ?kl½@,-"383

    .*  HSP  ,-*$% 1

 !"# +.

#&# ' ()*+,-./  .*.,01

#234 ,*.* 5 +

67'  +*,*,# HSP  ,8'9 !"# +  .

$8

' Fig. + .+ 



#:';5#:< => ?@A>B$%;CDB$E8'
9F##:<GH' HSP #Fig. +

Induction of HSP 1* by mi+d hyperthermia.

:< NK IJKL MNIOῌJK$E PQ"R@STUDVW'SBX< DY#Z[\]%43' Multho#,,**, ; Igueiredo et al., ,**3 

#P^#]%4 #:_4GH` HSP Pab MHC 9c5de% PIPabfg$EGh'i9#:< T ?@A>PI j$E% T?@A>Bkl%m8\8' no HSP 9Pab#:' HSP Q"R@P^pqZ!r
GH43' s` D9"#234Z#t#uv$X'/ "#$$%  HSP  !
HSP $Gh'nZ%u &wx0T'BX' y9zU{|#X'./ 2()*+},8'i9#:_4B~X< #g8 HSP*+#:' HSP $8'/+  HSP  !
HSP *+-9 t .*

 ,*

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 +/

 .,

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6W8 *+ +*+/%_<3 W' 2ZT<X'  38' HSP ,B!" +  .

s$8' 4  56

# HSP *+8'96#

HSP B !"#T< &# m#' %4 HSP B%4\'6 6 #, . HSP *+8'9uv$# +t .,+,/

B¡¢h'*+ 9 .* ,**+ *+ .* ,**+ *

 HSP 9 NK JKB%£#$%` s` ¤¥¦§ + ¨X'K©7Z*+ ,%£#% ¤¥¦?ª"«@¬!­89#Z HSP *+%uX' ®# CPK J
K ¯:;°± Z*+ + ,%£#% :;#Zuv$T*+X' .,*+  iHuv WHT_` :_4 HSP *+ HSP $²T/\ D$E ¤¥¦89 :;<TU:<³$T*+X'i9 ´={|Z
t$#>GH':µ?¶B@sH'
T2 VA·#¸%4 5Bῌ5¹#º»4 C1+B@sH' *+¼%½W# 384

' 0* ( ,*+*/, 

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89 # :" ;<=>?@A12 345*B" .+$ CDE CO,

 ; +***

ppm  .+$ EEFGHIJFK HSP L*M Maeda et al., ,**1# FM8" )IJ98+" HSP NO* HSP B ,-PQ7 " R)*S

T*FGUVWXY7 #0 ,- .*/0

Z%B" [\[@I6]^ [\[ " HSP _I`a8Jb" ?b[\[I,  \cdef ga89

/" ,**,# hij,

 , klI +&. kI HSP HI ,- . ]6" [\[ , @,U
V* # ,IFG

HSP Ym . IFG" nEopq[\[IF[\[ r Itoh and Noguchi, ,***" s!thu[s!t r" vw" ""xyz{ /6" ,**/" | /6" ,**/" #$ r /6" ,**2 }%%[\[ rUV&~a89 #  Y[\[ " ?b[\[I

Q* #:,IFG'()- . ]6 /6" ,**2 ;  6" ,*+*" HSP B*W
l}[+a89 #0+   !

+,n, @It, -. .*$ * -* , anpqI/a" ,-$ EI ,* o0a8Eopq[\[ V" -8nI[\[12a# 2t3I- a3 ¡¢£aV"
Table - I¤a4¥,an[\[B" 5 /*ῌ 6¦Y7# :" §78B

 --.-ῌ *MIa" ,B *ῌt82¨a# J" ,an HSP BHI ,a89# .76VB" ,IFGY7 HSP [\[ra.

¤a# 9I" ,t,*M.

HSP  ,a" §78 *ῌ I*b+ PQ7

]6" ©*¥tI

Itoh and Noguchi, ,***#0, "#$ % &'( )** +- ªL«[¬­®Ihij,@ Conthij, , k Mild hyper-

thermia I" \j¯i*nef[°±a# \j¯i²B +2* mῌmin ]6" + ³´ .I:;Dµ/ k" -* mῌmin ¶·²² # vV" v< + ª Fig. , I¤a4¥" ¸¹6a9ºidd»¤a# -Q¼" #$½:
Table - Ulcer area ratio and mortality of control and pre-treatedwith mild hyperthermia rats.
Control

Per-treated withMild hyperthermia

Ulcer area ratio/4.,ῌ +**ῌ

,40,ῌ* .24-ῌ

Mortality (ῌ)--4-ῌ 0/+2*ῌ */+2** P*.*/

385

  Fig. , Lactate in blood during treadmill running after mild hyperthermia.

 . mmolῌl  !"# +2* mῌmin $% --* mῌmin &'()*+ ,-. -/* mῌmin '/0.12345(678!"9: ;3 '234: HSP 1,-&'<=> ()?@:!AB@ % ,**2

1 &
1+ 

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W +ῌ+*

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j1k%@: Itoh et al., ,**3, ,*+* WYZ[\]^! .+ PQRS3 b 'E, l_i Wj1k%@: c"Bm PQRS3 b E_F`_i Wj2nc!$% _F` o%c !1p8!"
1,  

M-VAC !"

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q6rstuFva +, w M-VAC xy zJJ{|}~J ^[\Z]^ 
S|RY^ YZ[\]^ . _F`  .TO5PQRS3 yb 4:  j x .O5E , wE# 1# +* w.45E"#'9: E5.%@:1 2'$.
2-ῌ +,

 +*4: ¡WE

1W , wi 2¢E"$9: ') £¤¥"¦§¡W1¨./ῌ ' !$%©ª.«O¬­Wj'9: Yamada et al., ,**3xy®'"# ¯°±y ²³"´Fµ.E¶# 1) vaM·.!95
E @%Fµ E¢?"ZJ{Z' U95@%Fµ , ¸¹.PQRS3

º»4 HSP ¼½.§;45 @%ZJ{Z  .; !EWj¥'

386

$ 0* % ,*+*



2 

 HSP   





&'()*+, +-./! 0123 +4 567 8! 9:;<ῌ=>?@:ABC8 " DED! FGHI567 JK1LM*./N0
123+,*'! +4*OPQRST U2JK1LM 8V! QRS
TW9DOPXYD.Z[ῌ<\ " ]^! _1`ab! Pcd!

e! fgh-ijklm ALS! nopq r()37st

67 &'()9:Ivw:
HSP 8

B-() us:Gianluigi et al., ,**," OPQRSTx \ Hartl, +330" b1yz8?:

HSP {8*;EI|8! }E8~! m ?: "9I HSP \ b1yz-*?;Is: " w! b

1yz*88! I8 9 E; n8~8  
B8V! 'w: "3   
b1yz*! 22 z IV  HSP  I
?@ 8! 8EB8 "w! ;Eb1yzIV HSP ?@6'!"z L
M *! 22#$ \ %#22& I8 "b1yz' +  D6  HSP ()*! *T¡¢I
76 HSP  z?@ £+ D6¤I8~IC8 "¥#.I*  HSP ¦§D! 22E;¥#& D! ¥# 567 " 9  HSP ¦§! ¨D6! 9 
 HSP *! ©b1yz\ 9  HSP () ª8~C 8! ,- I««©8I z8 9 &'¬.­#I~
/560®   HSP w: "Burdon, R.H., Slater, A. and McMahon, M. (+32,) : Hyperthermia and the heat -shock proteinsof Hella cells. Br. J. Cancer, ./, 3/-ῌ30-.
Fedder, M.F. and Ho#man, G.E. (+333) : Heat-shock proteins, molecular chaperones and stressresponse ; evolutionary and ecological physiology. Ann. Rev. Physiol., 3,, -/+ῌ-00.
Gianluigi, F., Liana, T., Ilaria, B., Sergio, F., Roberto, I., Andrea, A., Giuseppe, R., Alessandro, N.,
Elena, C., Maria, A.V., Claudio, M., Massimo, F., Massimo. T., Alessandro, B. (,**,) : Protein
misfolding in Alzheimer’s and Parkinson’s disease ; genetics and molecular mechanisms.
Neurobiol. Aging, ,-, 3/1ῌ310.
Hartl, F.H. (+330) : Molecular chaperones in cellular protein folding. Nature, -2+, /1+ῌ/13.
Igueiredo, C., Wittmann, M., Wang, D., Dressel, R., Blasczyk, R. and Eizvesper, B. (,**3) : Heatshock protein 1* (HSP1*) induces cytotoxicity of Tῌhelper cells. Cell Communication and
Signaling, 1 (Suppl), A,2.

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387

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 +332 :,-./0$1  23  3 45 6789 HSP 1* :;<=> ?@A:BCD -- -2+ῌ-31.
Itoh, Y.H. and Noguchi, R. (,***) : Pre-treatment with mild whole-body heating prevents gastric ulcer induced by treatment and water-immersion stress in rats. Int. J. Hyperthermia,+0, +2-ῌ+3+.

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  ,**3 : ,KLT HSP 1*, HSP 0* ῌ 7  0  + # $ 01  ¡ 2 : -,,ῌ-,/.
Itoh, Y., Kazaoka, Y., Nitta, M., Yamada, Y. and Honda, N. (,**3) : Combining anti-tumor drugs
with mild hyperthermia increases the cytotoxic e#ects of drugs on human leukemia cells
in vitro. Molecular Medicine Reports, ,, .++ῌ.+/.
Itoh, Y., Yamada, Y., Kazaoka, Y., Ishiguchi, T. and Honda, N. (,*+*) : Combination of chemotherapy and mild hyperthermia enhances the anti-tumor e#ects of cisplatin and adriamycin in human bladder cancer T,. cells in vitro. Exp. Therapeutic Med., +, -+3ῌ-,-.
Lorimer, G. (+331) : Folding with a two-stroke motor. Nature, -22, 1,*ῌ1,+.
Maeda, M., Itoh, Y., Sugawara, M., Nagumo, H., Ichikawa, M., Miura, Y. and Hara, M. (,**1) :Changes in HSP (Heat Shock Protein) 1* due to CO, warm water bathing. J. Jpn. Soc.
Balneol. Climatol. Phys. Med., .*, ,,-ῌ,,0.
Multho#, G. (,**,) : Activation of natural killer cells by heat shock protein 1*. Int. J. Hyperthermia, +2, /10ῌ/2/.

¢£ +33. : %QF%RHST¤ +33. pp. +ῌ,0, \¥)¦ §¨Ritossa, F.M. (+30,) : A new pu$ng pattern induced by temperature shock and DNP in Drosophia. Experientia, +2, /1+ῌ/1-.
Welch, W. J. and Feramicso, J.R. (+32.) : Nuclear and localization of 1,,*** dalton heat shockprotein in heat-shocked mammalian cells. J. Biol. Chem., ,/3, ./*+ῌ./+-.
Yamada, Y., Itoh, Y., Aoki, S., Nakamura, K. and Honda, N. (,**3) : Preliminary results of
M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy foradvanced or metastatic transitional cell carcinoma of the urothelium. Cancer ChemotherPharmscol., 0., +*13ῌ+*2-.

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