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Synthetic interleukin 1 fragments with agonist activity
erkenbosch, F., Del Department
of Pharmacology, Medical Facuky. Free University, Van der Bowhorststrmt 7. 1081 BT A~terda~ aad * Se&-m of ~~~~~~0~.
Taie~et~~~~m~
~es~r~h ~epartmeat. ~aiversity Cant~a~ ~as~ita~, Base& S~~t~er~~nd
Nest responses to microbial, traumatic and chemical insults take the form of the acute phase response, in which the monolcine interleulcin-1 (IL-l) plays a central role. The acute phase response includes catabolic changes for the mob~~tion of metabolic substrates, pr~uction of specific substances by the liver, and central responses su fever, loss of appetite, slow wave sleep and others. Recently, circulating IL-1 has neuro-endocrine structures such as the hypothalamic-pituitary-adrenal axis (NPAA). been thought to control the initiation and pr~~sio~ of the IL-l driven acute involving circulating glucocorticoids. IL-1 irrduces ACTH and corticosterone secretion by a~~e~tati~a of ~retio~ of corticotropin releasing factor (CRF) from the hypothalamus. Our recent results demonstrate that other thalamic derived corticotrophic cell regulators such as vasopressin (AVP) are not involved. Since haIf of the the neurons have been shown to costore AVp, we advocate the view that I-IFAA activation in response to IL-I only evolves activation of CRF neurons not storing AVP. Selective effects of IL-I were also displays on secretion of ~~t~it~ hormones. While maximally activating the HPAA, no effects of peripheral administration of IL-1 were found on plasma concentrations of the anterior pituitary hormones prolactin, luteinizing hormone, follicle stim~lat~g hormone and of the iAte~~iate pituit~ hormone melanocyte stimulating ho~on~. ~urthe~ore, sy~pat~e~c activi only slightly increased as indicated by small and transient elevations of plasma epinephrine and norepin concentrations. These data lead us to conclude that the neUroeAdo&Ae effects of IL-1 are selective and clearly differ from stimuli generating a more general stress response. Our recent in situ byb~di~ti~~ expe~ments showed the presence of mRNA coding for IL-1 beta in Aeuro~s of the ad&t rat brain. These oe~roAs were pr~o~~antIy beats near circumventricular organs (e.g. nucleus arcuatus near the median eminence, preoptic area near the organurn vasculosum Iamina terminalis). Also hippocampal pyramidal cells, lining the choroid plexus and shown to express a high density of IL-1 receptors, contained IL-1 mRNA. Since circ~mveAt~cu1~ organs are ideally suited to sence circulating concentrations of peripheral hormones including i~~nede~ved products, we propose that the cmtrd actions of IL-l may be mediated through efferent circumventricular connections to the appropriate hmbic structures. This study was supported by the Dutch Royal Academy of Arts and Sciences.
oraschi, IX, Autos,
G., Tiara,
P,, Villa, IL., ~0~~~~. C. and ~~~~~a~ue, A.
Sciauo Research Center. Siena, Ifa&
Interleukin 1 (IL-l) is a family of cytokines deeply involved in the onset and development of the bos? reaction to invasion. IL-1 action ranges from ~~oge~~ty, h~tension, b~Qg~yce~a, i~~a~ato~ effects and alt~atio~ of
f cytokine cascades. 1 vo IL-l molecules have been -18. which are less than 30% homologous in their amino acid ties and possibly bind to the same receptor (Dinarello, 1989). nship in the human IL-l/3 protein and the existence of distinct peptides have been prepared, corresponding to well exposed EESNDK, in position 163-171 within the IL-1s molecule, was found of the entire IL-l& i.e. adjuvanticity, immunorestoration, tumor ammation-related activities such as pyrogenicity, hypoglycemia, TNF and lethality (Boraschi et al., 1988). Thus, the sequence in position 163-171 may represent one selectively involved in the immunostimulating activities of the parental molecule, but admatory effects. The relevance of the fragment 163-171 for the IL-IS immunostimulating the abiity of a monoclonal antibody against the VQGEESNDK peptide to block pyrogenicity, of IL-l@ in vivo. 163471 peptide was unable to bind to either the 80kD IL-1 receptor (IL-1R) present on T B cells. Thus, this fragment is not involved in the binding of IL-l/3 to its receptor and it ever, the 163-171 is associated and effectively internalized by both T and B cells through that IL-1 can activate cells by at least two mechanisms: one the IL-IR as primary activation signal, possibly through phophorylation of the IL-1R intracellular tion as necessary step for cell activation. The 163-171 in the latter activation mechanism but unable to trigger the
CA.. 1989. Adv. Immunol. 44,153. I).. Nendoni. I-... villa, I-.. Censti, S.. Bossu’. P., Ghiara, P., Presentini, R, Perin, F.. Frasca, D., Doria, G., Fomi, G.. uss~, T-, Giovarelli. M., Ghti, P., Bertini, R, Besedovsky, H.O., de1 Rey, \., Sipe, J-D.. Antoni, G., Silvestri, S., Tagliabue, A.,
mm, H.,
andtlow * , C., Heumann, FL, Lindholm,
D., Meyer, M. and Sprmger * *, M.
-FVanck-institute for Psychiatry, Dept. of Neurochemistry, Am Klopferspitz
18a, 8033 Planegg-Martinsried,
F. R. G.
NGF is a protein produced in limiting quantities by target tissues of NGF-responsive neurons and acts as a hit messenger. In the peripheral target areas of the NGF-responsive sympathetic and neuralneurons several cell types produce NGF: fibroblasts, epithelial cells, smooth muscle cells and In adult animals the non-neuronal cells ensheathing the axons of NGF-responsive neurons e NGF supply of these neurons. The major supply originates from their peripheral field of transection of the sciatic nerve (and with that the interruption of the NGF supply from the NGF synthesis increases dramatically. The long-lasting elevation of NGF-mRNA and NGF the site of lesion depends largely on the immigration of macrophages. Of the many cytokines produced macrophages, IL-1 was shown to be the predominant agent responsible for the sustained increased GF (~~olrn et al., NATURE 330, 658-9, 1987). Tumour necrosis factor and platelet derived growth factor which are also produced by macrophages have only a small effect on the NGF synthesis in cultured rat sciatic nerves- Thus, IL-1 plays an essential role in the promotion of the reactive increase in NGF synthesis after nerve lesion. In previous experiments other investigators had demonstrated that, in uitro, both astrocytes (Fontana et al., J.
of Pharmacology, Medical Facuky. Free University, Van der Bowhorststrmt 7. 1081 BT A~terda~ aad * Se&-m of ~~~~~~0~.
Taie~et~~~~m~
~es~r~h ~epartmeat. ~aiversity Cant~a~ ~as~ita~, Base& S~~t~er~~nd
Nest responses to microbial, traumatic and chemical insults take the form of the acute phase response, in which the monolcine interleulcin-1 (IL-l) plays a central role. The acute phase response includes catabolic changes for the mob~~tion of metabolic substrates, pr~uction of specific substances by the liver, and central responses su fever, loss of appetite, slow wave sleep and others. Recently, circulating IL-1 has neuro-endocrine structures such as the hypothalamic-pituitary-adrenal axis (NPAA). been thought to control the initiation and pr~~sio~ of the IL-l driven acute involving circulating glucocorticoids. IL-1 irrduces ACTH and corticosterone secretion by a~~e~tati~a of ~retio~ of corticotropin releasing factor (CRF) from the hypothalamus. Our recent results demonstrate that other thalamic derived corticotrophic cell regulators such as vasopressin (AVP) are not involved. Since haIf of the the neurons have been shown to costore AVp, we advocate the view that I-IFAA activation in response to IL-I only evolves activation of CRF neurons not storing AVP. Selective effects of IL-I were also displays on secretion of ~~t~it~ hormones. While maximally activating the HPAA, no effects of peripheral administration of IL-1 were found on plasma concentrations of the anterior pituitary hormones prolactin, luteinizing hormone, follicle stim~lat~g hormone and of the iAte~~iate pituit~ hormone melanocyte stimulating ho~on~. ~urthe~ore, sy~pat~e~c activi only slightly increased as indicated by small and transient elevations of plasma epinephrine and norepin concentrations. These data lead us to conclude that the neUroeAdo&Ae effects of IL-1 are selective and clearly differ from stimuli generating a more general stress response. Our recent in situ byb~di~ti~~ expe~ments showed the presence of mRNA coding for IL-1 beta in Aeuro~s of the ad&t rat brain. These oe~roAs were pr~o~~antIy beats near circumventricular organs (e.g. nucleus arcuatus near the median eminence, preoptic area near the organurn vasculosum Iamina terminalis). Also hippocampal pyramidal cells, lining the choroid plexus and shown to express a high density of IL-1 receptors, contained IL-1 mRNA. Since circ~mveAt~cu1~ organs are ideally suited to sence circulating concentrations of peripheral hormones including i~~nede~ved products, we propose that the cmtrd actions of IL-l may be mediated through efferent circumventricular connections to the appropriate hmbic structures. This study was supported by the Dutch Royal Academy of Arts and Sciences.
oraschi, IX, Autos,
G., Tiara,
P,, Villa, IL., ~0~~~~. C. and ~~~~~a~ue, A.
Sciauo Research Center. Siena, Ifa&
Interleukin 1 (IL-l) is a family of cytokines deeply involved in the onset and development of the bos? reaction to invasion. IL-1 action ranges from ~~oge~~ty, h~tension, b~Qg~yce~a, i~~a~ato~ effects and alt~atio~ of
f cytokine cascades. 1 vo IL-l molecules have been -18. which are less than 30% homologous in their amino acid ties and possibly bind to the same receptor (Dinarello, 1989). nship in the human IL-l/3 protein and the existence of distinct peptides have been prepared, corresponding to well exposed EESNDK, in position 163-171 within the IL-1s molecule, was found of the entire IL-l& i.e. adjuvanticity, immunorestoration, tumor ammation-related activities such as pyrogenicity, hypoglycemia, TNF and lethality (Boraschi et al., 1988). Thus, the sequence in position 163-171 may represent one selectively involved in the immunostimulating activities of the parental molecule, but admatory effects. The relevance of the fragment 163-171 for the IL-IS immunostimulating the abiity of a monoclonal antibody against the VQGEESNDK peptide to block pyrogenicity, of IL-l@ in vivo. 163471 peptide was unable to bind to either the 80kD IL-1 receptor (IL-1R) present on T B cells. Thus, this fragment is not involved in the binding of IL-l/3 to its receptor and it ever, the 163-171 is associated and effectively internalized by both T and B cells through that IL-1 can activate cells by at least two mechanisms: one the IL-IR as primary activation signal, possibly through phophorylation of the IL-1R intracellular tion as necessary step for cell activation. The 163-171 in the latter activation mechanism but unable to trigger the
CA.. 1989. Adv. Immunol. 44,153. I).. Nendoni. I-... villa, I-.. Censti, S.. Bossu’. P., Ghiara, P., Presentini, R, Perin, F.. Frasca, D., Doria, G., Fomi, G.. uss~, T-, Giovarelli. M., Ghti, P., Bertini, R, Besedovsky, H.O., de1 Rey, \., Sipe, J-D.. Antoni, G., Silvestri, S., Tagliabue, A.,
mm, H.,
andtlow * , C., Heumann, FL, Lindholm,
D., Meyer, M. and Sprmger * *, M.
-FVanck-institute for Psychiatry, Dept. of Neurochemistry, Am Klopferspitz
18a, 8033 Planegg-Martinsried,
F. R. G.
NGF is a protein produced in limiting quantities by target tissues of NGF-responsive neurons and acts as a hit messenger. In the peripheral target areas of the NGF-responsive sympathetic and neuralneurons several cell types produce NGF: fibroblasts, epithelial cells, smooth muscle cells and In adult animals the non-neuronal cells ensheathing the axons of NGF-responsive neurons e NGF supply of these neurons. The major supply originates from their peripheral field of transection of the sciatic nerve (and with that the interruption of the NGF supply from the NGF synthesis increases dramatically. The long-lasting elevation of NGF-mRNA and NGF the site of lesion depends largely on the immigration of macrophages. Of the many cytokines produced macrophages, IL-1 was shown to be the predominant agent responsible for the sustained increased GF (~~olrn et al., NATURE 330, 658-9, 1987). Tumour necrosis factor and platelet derived growth factor which are also produced by macrophages have only a small effect on the NGF synthesis in cultured rat sciatic nerves- Thus, IL-1 plays an essential role in the promotion of the reactive increase in NGF synthesis after nerve lesion. In previous experiments other investigators had demonstrated that, in uitro, both astrocytes (Fontana et al., J.