Invited Symposium: Cytokines, Monoamines and Behavior


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Molecular Mechanisms in Interleukin-1beta-induced Anorexia

Contact Person: Carlos R Plata-Salaman (crps@udel.edu)


Interleukin-1beta (IL-1) induces anorexia by direct action in the CNS. The microstructural analysis of the anorexia induced by IL-1 shows that this cytokine induces anorexia at estimated pathophysiological concentrations in the cerebrospinal fluid (CSF) through a reduction of meal size (MS) and meal duration (MD); feeding rate (MS/MD) decreases and this indicates a greater effect on MS than on MD duration. Meal frequency is not affected by doses of IL-1 that yield estimated pathophysiological concentrations in the CSF. IL-1-induced anorexia is completely blocked by the IL-1 receptor antagonist (IL-1Ra). This suggests specificity of action and a receptor-mediated phenomenon. The intracerebroventricular pretreatment with an antisense (but not sense) phosphothio-oligodeoxynucleotide to the IL-1 receptor type I (IL-1RI) also inhibits IL-1-induced anorexia. These data indicate that IL-1RI (signaling receptor) is involved in IL-1-induced anorexia. The precise changes in meal parameters associated with IL-1-induced anorexia suggest specific action of IL-1 on various mechanisms.

Interleukin-1-induced anorexia may be involved in disease-associated anorexia. Patients with cancer can exhibit the early satiety phenomenon which is dependent on a decrease of MS (and MD); this pattern is similar to that observed with IL-1 administration in animals at doses that yield estimated pathophysiological concentrations in the CSF.

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Hypothalamic Mechanisms

Interleukin-1 suppresses the neuronal activity of the glucose-sensitive neurons in the LHA, while induces excitation of the glucose-sensitive neurons in the VMN. These effects are reversible and specific because IL-1 has no effect on the glucose-insensitive neurons in the LHA and VMN. The IL-1-induced long-lasting modulation of hypothalamic neuronal activity is consistent with the anorectic pattern induced by IL-1. Data also suggest that the long latency and duration of action of IL-1 on neuronal activity is associated with the activation of intracellular mediators.

Interleukin-1 is capable of modifying the normal hypothalamic neurotransmitter and neuropeptide profiles and this may result in anorexia. The intracerebroventricular administration of IL-1 blocks the feeding-enhancing effect of neuropeptide Y (an endogenous potent feeding-stimulating factor). This IL-1-neuropeptide Y interaction may have significant clinical implications. This is because hypothalamic concentration and release of neuropeptide Y may change during disease, being reduced in anorectic models and up-regulated during obesity. IL-1 and other cytokines activate the hypothalamic-pituitary-adrenal gland axis. Leptin (a member of the long-chain helical cytokine family which includes IL-6) induces anorexia by reducing MS, and leptin has significant interactions with neuropeptide Y and the hypothalamic-pituitary-adrenal gland axis. Leptin and IL-1 can induce each other, and therefore, reciprocal IL-1-leptin-neuropeptide Y-CRF-ACTH-glucocorticoid interactions are important in disease-associated anorexia.

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Ion Channel Modulation by IL-1

Interleukin-1 modulates hypothalamic neuronal activity through various mechanisms including the involvement of calcium permeability and intracellular mediators. Pathophysiological concentrations of IL-1 inhibit the neuronal voltage-gated calcium channel currents in acutely isolated neurons. IL-1Ra completely blocks the effects of IL-1 on the neuronal calcium channel currents. Thus, this action of IL-1 on acutely isolated neurons involves the IL-1RI. Other data showed that this IL-1 receptor is associated with the activation of protein kinase C. Modulation of the inward calcium channel current by IL-1 may play a role in regulating neuronal excitability and neurotransmitter release-associated mechanisms during specific pathological processes associated with increased brain/CSF concentrations of IL-1.

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Indirect G-protein Modulation

Neurotransmitter and neuropeptide G-protein-coupled receptors participate in the modulation of feeding. VMN neurons exhibit an array of G-protein a-subunit subclasses. Evidence indicate that the G-protein a-subunit subclass GaO is critical for the integrative modulation of normal feeding behavior, and that changes in its activity are associated with modifications of feeding.

The chronic brain microinfusion of IL-1 (at doses that yield estimated pathophysiological concentrations) induces a dose-dependent long-term anorexia associated with a dose-dependent decrease in VMN G-protein GaO common protein content. Heat-inactivated IL-1 had no effect, and IL-1Ra blocked the IL-1-induced anorexia and the effects of IL-1 on the G-protein a-subunit VMN profile. These data indicate specificity of action and receptor mediated phenomena. Thus, the evidence is consistent with the model of anorexia associated with changes in the G-protein a-subunit subclass GaO. Receptors coupled to the GaO include receptors for endogenous peptides that are potent stimulators of feeding; IL-1-induced reduction in the levels of their transducer could result in anorexia.

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Cytokine Systems

A combined approach using computerized meal pattern analyses with molecular biology approaches has been used to characterize IL-1-induced anorexia. The profile of cytokine system components [ligands, receptors, transducing molecules, endogenous inhibitors; for example, IL-1alpha and IL-1beta, IL-1 receptor types I and II (IL-1RI and IL-1RII), IL-1 receptor accessory proteins I (IL-1R AcP I or membrane bound) and II(IL-1R AcP II or soluble form), and IL-1 receptor antagonist (IL-1Ra)] has been characterized in specific brain region samples with competitive-PCR, sensitive and specific RNase protection assays and immunoblots. In the same IL-1-induced anorectic animals, both neuropeptide and cytokine profiles have been studied. The overall significance from these studies is that paracrine interactions within brain regions represent a predominant mode of cytokine action in the CNS, that is, IL-1 is capable of inducing anorexia via local production of cytokines in the brain. This production occurs in all brain regions examined with predominance in the hypothalamus.

The chronic intracerebroventricular microinfusion of IL-1 (at doses that yield estimated pathophysiological concentrations in the CSF) increases IL-1, IL-1RI, IL-1R AcP II (soluble form), IL-1Ra, TNF-alpha and TGF-beta1 mRNAs in the hypothalamus obtained from anorectic rats responding to IL-1. IL-1-induced IL-1 system and ligand (IL-1, TNF-alpha and TGF-beta1) mRNA profiles were highly intercorrelated in the same samples, and levels of membrane bound IL-1R AcP and TGF-alpha mRNAs did not change. Heat-inactivated IL-1 had no effect. The data suggest the operation of an IL-1 feedback system (IL-1/IL-1RI/IL-1R Acp II/IL-1RII/IL-1Ra), and potential cytokine-cytokine interactions with positive (IL-1 and TNF) and negative (IL-1Ra, TGF-beta1 modulating IL-1/TNF-alpha) feedback. The data also suggest brain region autoregulatory positive and negative feedback subsystems and cytokine to cytokine and cytokine to neuropeptide interactions. The magnitude of anorexia induced by IL-1 may depend on the ratio between stimulatory and inhibitory cytokines. This is supported by data obtained using bacterial-derived products [e.g., lipopolysaccharide (LPS) from Gram-negative and muramyl dipeptide (MDP) from Gram-positive bacteria] which stimulate IL-1 and other cytokines production. LPS and MDP play a pivotal role in the generation of neurological and neuro-inflammatory/immunological responses during bacterial infections. LPS and MDP action involves cytokines. However, LPS is significantly more potent than MDP in inducing anorexia and in up-regulating pro-inflammatory cytokines (IL-1 and TNF-alpha) mRNAs in brain regions including the hypothalamus; MDP is more potent in up-regulating anti-inflammatory cytokines (IL-1Ra and TGF-â1) mRNAs. Thus, it is possible that the magnitude of anorexia induced by LPS and MDP may involve the ratio between stimulatory and inhibitory cytokines.

Interleukin-1-induced anorexia may be involved in disease-associated anorexia. For example, anorexia in rats bearing prostate adenocarcinoma tumor cells is associated with an up-regulation of IL-1 mRNA in peripheral organs and discrete brain regions (including the hypothalamus) of the same rats responding to tumor formation in the periphery. This local production of IL-1 within brain regions can be independent from the profiles in the periphery, that is, local paracrine/autocrine interactions can result in local cytokine production and action within the CNS resulting in the induction of neurological/neuropsychiatric manifestations including anorexia. This, in fact, represents a novel model of disease-associated anorexia, that is, local production of IL-1 (and other specific cytokines) in the brain could be involved in the induction of anorexia or exacerbation of anorexia during acute and chronic disease.

Acknowledgments: The author acknowledges the support from the National Institutes of Health. REFERENCES (For other pertinent references see home page at: www.udel.edu/Cytokines)

  1. Flynn, M.C., T.R. Scott, T.C. Pritchard and C.R. Plata-Salamán. Mode of action of OB protein (leptin) on feeding. American Journal of Physiology 275:R174-R179, 1998.
  2. Gayle, D., S.E. Ilyin, M.C. Flynn and C.R. Plata-Salamán. Lipopolysaccharide (LPS)- and muramyl dipeptide (MDP)-induced anorexia during refeeding following acute fasting: Characterization of brain cytokine and neuropeptide systems mRNAs. Brain Research 795:77-86, 1998.
  3. Gayle, D., S.E. Ilyin and C.R. Plata-Salamán. Central nervous system IL-1b system and neuropeptide Y mRNAs during IL-1b-induced anorexia in rats. Brain Research Bulletin 44:311-317, 1997.
  4. Ilyin, S.E., I. González-Gómez, F.H. Gilles and C.R. Plata-Salamán. Interleukin-1a (IL-1a), IL-1b, IL-1 receptor type I, IL-1 receptor antagonist and TGF-b1 mRNAs in pediatric astrocytomas, ependymomas and primitive neuroectodermal tumors. Molecular and Chemical Neuropathology 33:125-137, 1998.
  5. Plata-Salamán, C.R. Brain injury and immunosuppression. Nature Medicine 4:768-769, 1998.
  6. Plata-Salamán, C.R. Cytokines and feeding. News in Physiological Sciences 13:304-310, 1998. Plata-Salamán, C.R. Hypothalamus and the control of feeding: fifteen decades of direct association. Nutrition 14:67-70, 1998.
  7. Plata-Salamán, C.R. and S.E. Ilyin. IL-1b-induced modulation of the hypothalamic IL-1b system, TNF-a and TGF-b1 mRNAs in obese (fa/fa) and lean (Fa/Fa) Zucker rats: Implications to IL-1b feedback systems and cytokine-cytokine interactions. Journal of Neuroscience Research 49:541-550, 1997.
  8. Plata-Salamán, C.R., S.E. Ilyin and Dave Gayle. Brain cytokine mRNAs in anorectic rats bearing prostate adenocarcinoma tumor cells. American Journal of Physiology 275:R566-R573, 1998.
  9. Plata-Salamán, C.R., S.E. Ilyin, D. Gayle and M.C. Flynn. Gram-negative and Gram-positive bacterial products induce differential cytokine profiles in the brain: Analysis using an integrative molecular-behavioral in vivo model. International Journal of Molecular Medicine 1:387-397, 1998.
  10. Plata-Salamán, C.R., C.D. Wilson and J.M.H. ffrench-Mullen. In vivo IL-1b-induced modulation of G-protein aO subunit subclass in the hypothalamic ventromedial nucleus: Implications to IL-1b-associated anorexia. Molecular Brain Research 58:188-194, 1998.

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Plata-Salaman, C; (1998). Molecular Mechanisms in Interleukin-1beta-induced Anorexia. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/anisman/plata-salaman0321/index.html
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