Interleukin-1α (IL-1α), IL-1β, IL-1 receptor type I, IL-1 receptor antagonist, and TGF-β1 mRNAs in pediatric astrocytomas, ependymomas, and primitive neuroectodermal tumors

Interleukin-1α (IL-1α), IL-1β, interleukin-1 receptor type I (IL-1RI, signaling receptor), and IL-1 receptor antagonist (IL-1Ra, endogenous inhibitor) are pivotal components of the IL-1 system. IL-1 and other cytokines induced by IL-1, such as TGF-β1, may participate in the growth of various tumor cells. In children, primary nervous system tumors represent the most common solid malignancy. We investigated the levels of IL-1α, IL-1β, IL-1RI, IL-1Ra, and TGF-β1 mRNAs in pediatric astrocytomas (n=19), ependymomas (n=13), and primitive neuroectodermal tumors (n=22) using sensitive and specific RNase protection assays. The data show a significant distinct cytokine mRNA profile among brain tumor types. Pilocytic, nonpilocytic, and anaplastic astrocytomas have significant increased levels of IL-1β, IL-1RI, and TGF-β1 mRNAs, but low levels of IL-1Ra mRNA; this may have implications for an IL-1β feedback system and IL-1β?TGF-β1 interactions in astrocytomas. Ependymomas show increased levels of IL-1α and IL-1β mRNAs associated with low levels of IL-1Ra mRNA; primitive neuroectodermal tumors do not exhibit increased levels of any cytokine component examined. The data also suggest that a dysregulation of the balance between stimulatory and inhibitory cytokines may be involved in the growth and development of brain tumors via autocrine/paracrine mechanisms.     

Interleukin 1-β- and tumor necrosis factor-α-mediated regulation of ICAM-1 gene expression in astrocytes requires protein kinase C activity

Several adhesion molecules including intracellular adhesion molecule-1 (ICAM-1) are expressed by astrocytes, the predominant glial cell of the central nervous system (CNS). Such molecules are important in the trafficking of leukocytes to sites of inflammation, and in lymphocyte activation. ICAM-1 is constitutively expressed by neonatal rat astrocytes, and expression is enhanced by the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), with IL-1β and TNF-α being the strongest inducers. In this study, we have examined the nature of the second messengers involved in ICAM-1 gene expression induced by the cytokines IL-1β and TNF-α. Our results indicate that stimuli related to protein kinase C (PKC) such as the phorbol ester phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 increase ICAM-1 mRNA expression, whereas cyclic nucleotide analogs and PKA agonists have no effect. Pharmacologic inhibitors of PKC such as H7, H8, and calphostin C inhibit ICAM-1 gene expression inducible by IL-1β and TNF-α. Prolonged treatment of astrocytes with PMA results in a time-dependent downregulating of the PKC isoforms α, δ, and ?, and a concomitant diminution of ICAM-1 mRNA expression induced by IL-1β, TNF-α, and PMA itself at specific time points post-PMA treatment. These data, collectively, demonstrate a role for various PKC isoforms in IL-1β and TNF-α enhancement of ICAM-1 gene expression in rat astrocytes. © 1995 Wiley-Liss, Inc.     

Central Nervous System IL-1β System and Neuropeptide Y mRNAs During IL-1β-induced Anorexia in Rats

Interleukin-1β (IL-1β) induces anorexia and neuropeptide Y (NPY) increases feeding by direct action in the central nervous system (CNS). IL-1β, depending on the dose, attenuates or blocks NPY-induced feeding. This suggests that IL-1β-NPY interactions may be involved in IL-1β-induced anorexia. Here, RNase protection assays were used to investigate the effects of the chronic intracerebroventricular (ICV) administration of IL-1β (at a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid) on mRNA levels of IL-1β system components and NPY in the cerebellum, parietofrontal cortex, hippocampus, hypothalamus, and midbrain. The results show that the chronic ICV administration of IL-1β (8.0 ng/24 h for 72 h) differentially induced IL-1β system components across brain regions in anorectic rats. IL-1β mRNA and IL-1 receptor antagonist (IL-1Ra) mRNA were induced similarly, exhibiting highest and lowest expression levels in the hypothalamus and hippocampus, respectively. IL-1 receptor type I (IL-1RI) mRNA and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA were also induced in the hypothalamus and cerebellum. NPY mRNA expression showed a small, but significant decrease in the hypothalamus. Heat-inactivated IL-1β (8.0 ng/24 h for 72 h) had no effect on the behavioral or molecular profiles. The results suggest that endogenous upregulation of IL-1β contributes to IL-1β-induced anorexia, and that modification of NPY mechanisms also may be involved.     

Multiple sclerosis: myelin basic protein induced mRNA expression of proinflammatory cytokines in mononuclear cells is suppressed by interferon-β 1b in vitro

Beta-interferon (IFN-β) is a promising treatment in multiple sclerosis (MS), reducing the exacerbation rate and MRI lesion burden, as well as the disease progression in relapsing-remitting MS. IFN-β was originally defined by its antiviral effects, but the interest has recently been focused on its immunomodulatory properties. Myelin basic protein (MBP) is one of several autoantigens considered to be the target for autoaggressive immune responses, which eventually might lead to the development of MS. To study in-vitro effects of IFN-β1b on MBP induced cytokine expression, mRNA for the Th1 cytokines IFN-γ and TNF-α, the Th2 related IL-4 and IL-6, the cytolytic perforin and the immune response downregulating TGF-β was measured with in situ hybridization after culture of blood mononuclear cells (MNC) in the presence and absence of MBP. Numbers of cells expressing IFN-γ, TNF-α, perforin and IL-4 mRNA were significantly suppressed after culture with 10 U/ml IFN-β1b. No such effect was seen on MBP induced IL-6 or TGF-β mRNA expression. These observations suggest that one of the major effects of IFN-β1b is the induction of a shift in the cytokine mRNA profile towards a more immunosuppressive pattern. In parallel in vitro tests, the control substance dexametasone (40 μg/ml) reduced the numbers of cells expressing mRNA for all cytokines under study with the exception of TGF-β, to an extent equal to or even more pronounced than IFN-β1b.     

Regulation of brain interleukin-1β (IL-1β) system mRNAs in response to pathophysiological concentrations of IL-1β in the cerebrospinal fluid

Interleukin-1β (IL-1β) is released during pathophysiological processes. IL-1β induces neurological manifestations when administered into the cerebrospinal fluid (CSF) at pathophysiological concentrations detected during central nervous system (CNS) infections and other neurological disorders. In the present study, we investigated the regulation of the IL-1β system in the CNS in response to the chronic intracerebroventricular (icv) microinfusion of IL-1β at estimated pathophysiological concentrations in the CSF. IL-1 receptor type I (IL-1RI), IL-1 receptor antagonist (IL-1Ra), and IL-1β mRNAs were determined by sensitive RNase protection assays in brain target regions for IL-1β (cerebellum, parieto-frontal cortex, hippocampus, and midbrain). The results show that chronic icv microinfusion of IL-1β induced significant anorexia, increased the cerebellar IL-1RI mRNA content, increased IL-1Ra and IL-1β mRNAs levels in the cerebellum > midbrain > cortex > hippocampus, and induced profiles of IL-1RI mRNA, IL-1Ra mRNA, and IL-1β mRNA that were highly intercorrelated. On the other hand, levels of rat glyceraldehyde 3-phosphate dehydrogenase mRNA and 18S rRNA were fairly constant, and heat-inactivated IL-1β had no effect on food intake or on IL-1RI, IL-1Ra, and IL-1β mRNAs levels in any brain region. The data suggest the operation of an IL-1β feedback system (IL-1β/IL-1Ra/IL-1RI) in brain regions. Dysregulation of the CNS IL-1β feedback system may have pathophysiological significance. This may be reflected, for example, in the pathogenicity and severity of neurological diseases, such as CNS infections.     

Implication of Akt‐dependent Prp19α/14‐3‐3β/Cdc5L complex formation in neuronal differentiation

PRP19α and CDC5L are major components of the active spliceosome. However, their association process is still unknown. Here, we demonstrated that PRP19α/14‐3‐3β/CDC5L complex formation is regulated by Akt during nerve growth factor (NGF)‐induced neuronal differentiation of PC12 cells. Analysis of PRP19α mutants revealed that the phosphorylation of PRP19α at Thr 193 by Akt was critical for its binding with 14‐3‐3β to translocate into the nuclei and for PRP19α/14‐3‐3β/CDC5L complex formation in neuronal differentiation. Forced expression of either sense PRP19α or sense 14‐3‐3β RNAs promoted NGF‐induced neuronal differentiation, whereas down‐regulation of these mRNAs showed a suppressive effect. The nonphosphorylation mutant PRP19αT193A lost its binding ability with 14‐3‐3β and acted as a dominant‐negative mutant in neuronal differentiation. These results imply that Akt‐dependent phosphorylation of PRP19α at Thr193 triggers PRP19α/14‐3‐3β/CDC5L complex formation in the nuclei, likely to assemble the active spliceosome against neurogenic pre‐mRNAs. © 2010 Wiley‐Liss, Inc.     

The role of tumour necrosis factor alpha and soluble tumour necrosis factor alpha receptors in the symptomatology of schizophrenia

Background Immunological mechanisms may be responsible for the development and maintenance of schizophrenia symptoms. Aim The aim of this study is to measure tumour necrosis factor-alpha (TNF-α), soluble tumour necrosis factor-alpha receptor I (sTNF-αRI), and soluble tumour necrosis factor-alpha receptor II (sTNF-αRII) levels in patients with schizophrenia and healthy individuals, and to determine their relationship with the symptoms of schizophrenia. Methods Serum TNF-α, sTNF-αRI and sTNF-αRII levels were measured. The Positive and Negative Syndrome Scale (PANSS) was administered for patients with schizophrenia (n?=?35), and the results were compared with healthy controls (n?=?30). Hierarchical regression analyses were undertaken to predict the levels of TNF-α, sTNF-αRI and sTNF-αRII. Results No significant difference was observed in TNF-α levels, but sTNF-αRI and sTNF-αRII levels were lower in patients with schizophrenia. Serum sTNF-αRI and sTNF-αRII levels were found to be negatively correlated with the negative subscale score of the PANSS, and sTNF-αRI levels were also negatively correlated with the total score of the PANSS. Smoking, gender, body mass index were not correlated with TNF-α and sTNF-α receptor levels. Conclusions These results suggest that there may be a change in anti-inflammatory response in patients with schizophrenia due to sTNF-αRI and sTNF-αRII levels. The study also supports low levels of TNF activity in schizophrenia patients with negative symptoms.     

Transforming growth factor-βs inhibit mitogen-stimulated proliferation of astrocytes

We have studied the influence of three members of the transforming growth factor-β (TGF-β) family of multifunctional growth factors on the proliferation of cultured astrocytes isolated from newborn mouse cerebral cortex. Although TGF-βs 1, 2, and 3 cause only a small reduction in the low level of astrocyte proliferation occurring in chemically defined medium, they each inhibit the effects of five astrocyte mitogens (bFGF, EGF, PDGF, IL-1α, and IL-2). Inhibition is observed when astrocytes are exposed to mitogen and TGF-r3 at the same time and when they are exposed to TGF-β prior to, and separately from, mitogen. This latter effect appears to be due to the binding of TGF-βs to astrocyte-secreted extracellular matrix. These findings raise the possibility that TGF-β may co-operate with other growth factors to control astrocyte proliferation in vivo.     

TNF-α and TGF-β act synergistically to kill Schwann cells

Interactions between cytokines and Schwann cells (SC) are important in development, repair, and disorders of the peripheral nervous system (PNS). Tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) are two prominent cytokines which may be involved in these processes and their gene products are upregulated in some experimental neuropathies. This study focuses on thein vitro effects of these cytokines, both singly and in combination, on cultured SC. Expression of both Type I and Type II TNF-α receptors was demonstrated on the SC surface by immunocytochemistry. Treatment of SC with a combination of TNF-α plus TGF-β causes significant detachment and cell death while treatment with each cytokine alone is not significantly cytotoxic. When compared with control cultures, SC treated with the combination of cytokines exhibit an increase in the number of cells with condensed nuclei and evidence of DNA fragmentation, characteristics consistent with cells undergoing programmed cell death. Thus, TNF-α plus TGF-β induce SC loss of adhesion which is predominantly due to cell death. Apoptotic mechanisms are likely to contribute to some extent to this cell death. These findings provide in vitro evidence to support the hypothesis that cytokines can directly damage SC in PNS disorders. J. Neurosci. Res. 53:747–756, 1998. © 1998 Wiley-Liss, Inc.     

Transforming growth factor-β1 suppresses autoantigen-induced expression of pro-inflammatory cytokines but not of interleukin-10 in multiple sclerosis and myasthenia gravis

Multiple sclerosis (MS) is associated with high levels of circulating T lymphocytes that respond to the myelin antigens myelin basic protein (MBP) and proteolipid protein (PLP) by producing various cytokines including interferon-γ (IFN-γ) that makes MS worse and transforming growth factor-β (TGF-β), an endogenously produced immunosuppressant that might act beneficially. To further define the role of TGF-β in MS, we examined the effects of recombinant TGF-β1 (rTGF-β1) on autoantigen-mediated regulation of cytokines in MS and myasthenia gravis (MG). Blood mononuclear cells (MNC) were cultivated with or without rTGF-β1, and with or without autoantigen or the recall antigen PPD. MNC expressing cytokine mRNA were detected after in situ hybridization with radiolabeled cDNA oligonucleotide probes. Femtogram concentrations of rTGF-β1 suppressed MBP-, PLP- and PPD-induced upregulation of IFN-γ, IL-4, IL-6, tumor necrosis factor-α (TNF-α), TNF-α and perforin in MS, and acetylcholine receptor (AChR)-induced augmentation of these pro-inflammatory cytokines in MG, but had no effects on autoantigen- or PPD-induced expression of IL-10 or TGF-β itself. rTGF-β1 also suppressed numbers of myelin antigen-reactive IFN-γ- and IL-4-secreting cells in MS and AChR-reactive IFN-γ and IL-4 secreting cells in MG. The selective suppressive effects of TGF-β1 on autoantigen-induced upregulation of pro-inflammatory cytokines makes TGF-β1 attractive as a treatment alternative in MS and MG.     

Interleukin-1β, but not IL-1α, mediates nerve growth factor secretion from rat astrocytes via type I IL-1 receptor

In astrocytes, nerve growth factor (NGF) synthesis and secretion is stimulated by the cytokine interleukin-1β (IL-1β). In the present study, the role of IL-1 receptor binding sites in the regulation of NGF release was evaluated by determining the pharmacological properties of astroglially localized IL-1 receptors, and, by comparing the effects of both the agonists (IL-1α and IL-1β) and the antagonist (IL-1ra)—members of the IL-1 family on NGF secretion from rat neonatal cortical astrocytes in primary culture. Using receptor-binding studies, binding of [¹²⁵I] IL-1β to cultured astrocytes was saturable and of high affinity. Mean values for the K_D and B_max were calculated to be 60.7±7.4 pM and 2.5±0.1 fmol mg^-1 protein, respectively. The binding was rapid and readily reversible. IL-1 receptor agonists IL-1α (K_i of 341.1 pM) and IL-1β (K_i 59.9 pM), as well as the antagonist IL-1ra (K_i 257.6 pM), displaced specific [¹²⁵I] IL-1β binding from cultured astrocytes in a monophasic manner. Anti-IL-1RI antibody completely blocked specific [¹²⁵I] IL-1β binding while anti-IL-1RII antibody had no inhibitory effect. Exposure of cultured astrocytes to IL-1α and IL-1β revealed the functional difference between the agonists in influencing NGF release. In contrast to IL-1β (10 U/ml), which caused a 3-fold increase in NGF secretion compared to control cells, IL-1α by itself had no stimulatory action on NGF release. The simultaneous application of IL-1α and IL-1β elicited no additive response. IL-1ra had no effect on basal NGF release but dose-dependently inhibited the stimulatory response induced by IL-1β. We concluded that IL-1β-induced NGF secretion from cultured rat cortical astrocytes is mediated by functional type I IL-1 receptors, whereas IL-1α and IL-1ra, in spite of their affinity for IL-1RI, have no effect on NGF secretion from these cells. Type II IL-1R is not present on rat neonatal cortical astrocytes.     

Increased transforming growth factor-β, interleukin-4, and interferon-γ in multiple sclerosis

The inflammatory nature of multiple sclerosis (MS) implicates the participation of immunoregulatory cytokines, including the T-helper type 1 (Th1) cell–associated interferon-σ (IFN-σ), the Th2 cell–related interleukin-4 (IL-4), and the immune response–downregulating cytokine transforming growth factor-β (TGF-β), but proof for their involvement in MS has been lacking. By adopting in situ hybridization with complementary DNA oligonucleotide probes for human IFN- IL-4, and TGF-β, the expression of mRNA for these cytokines was detected in mononuclear cells (MNC) from blood and cerebrospinal fluids. Strongly elevated levels of MNC expressing all three cytokines were found in peripheral blood and at even higher frequencies in cerebrospinal fluid from untreated patients with MS and optic neuritis, i.e., a common first manifestation of MS, compared with patients with other neurological diseases and healthy subjects. In MS and optic neuritis, IL-4 mRNA expressing cells predominated, followed by TGF-β– and IFN-σ–positive cells. Control patients with myasthenia gravis had similarly elevated levels of IFN-σ and TGF-β mRNA expressing blood MNC but lower numbers of IL-4–positive cells. No or slight disability of MS was associated with high levels of TGF-β mRNA expressing cells, while MS patients with moderate or severe disability had high levels of IFN-σ–positive cells. IFN-σ and TGF-β may have opposing effects in MS, and treatments inhibiting IFN-σ and/or promoting TGF-β might ameliorate MS.     

ROCK抑制剂法舒地尔对BV2小胶质细胞极化的影响

目的 探讨Rho激酶(Rho-associated kinase,ROCK)抑制剂法舒地尔(Fasudil)对BV2小胶质细胞极化的影响.方法 免疫荧光观察细胞形态及ROCK2表达水平;乳酸脱氢酶(Lactate dehydrogenase,LDH)细胞毒性检测试剂盒检测Fasudil对细胞的毒性作用;逆转录聚合酶链反...     

黄芩苷对海人酸致痫小鼠海马白细胞介素-1β及肿瘤坏死因子-α表达的影响

目的 探讨黄芩苷对海人酸诱导的小鼠癫痫持续状态后海马组织白细胞介素-1 β(IL-1β)、肿瘤坏死因子-α(TNF-α)表达的影响.方法 将54只ICR雄性小鼠随机分为对照组、癫痫持续状态(SE)组、黄芩苷治疗组,每组18只.采用侧脑室注入海人酸建立小鼠癫痫持续状态模型.HE染色观察黄芩苷对小鼠癫痫持续状态后海马神经细胞的形态学影响.通过RT-PCR和Western blot分别检测小鼠海马组织中IL-1β mRNA、TNF-α mRNA及IL-1β、TNF-α蛋白的表达量.结果 黄芩苷明显改善了SE后小鼠海马组织的病理形态学,并且可降低IL-1β、TNF-α的表达(P＜0.05).结论 黄芩苷可能通过降低癫痫鼠海马组织中IL-1 β、TNF-α的表达发挥抗炎作用,从而对脑组织进行保护.     

Epidermal growth factor (EGF), transforming growth factor-α (TGF-α), and basic fibroblast growth factor (bFGF) differentially influence neural precursor cells of mouse embryonic mesencephalon

Growth factors are key elements in the process of neural cell differentiation. We examined the effects of classical mitogens on neural precursor cells, by culturing mouse cells of the embryonic (13.5 days postcoitum) mesencephalon and treating them with epidermal growth factor (EGF), transforming growth factor-β (TGF-β), basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and transforming growth factor-β (TGF- β). Our initial results show that EGF, TGF-α or bFGF, but not NGF or TGF-β, induced general proliferation of the cultured cells, followed by formation of colonies. Combinations of these three growth factors suggest that most cells with the capacity to form colonies responded to EGF, TGF-α, or bFGF. The number of colonies increased significantly when EGF, but not TGF-α, was used in combination with bFGF. Furthermore, a population responding only to EGF + bFGF was detected in the dorsal mesencephalon. The colony-forming activity of bFGF was dependent on insulin, but bFGF and insulin cooperation was indirect since we could not observe colony formation in subcultures of cells derived from colonies, even in the presence of insulin. Cells obtained from our colonies displayed neuronal and glial morphology and expressed markers of both neurons and astrocytes; nestin, a marker of neural precursor cells was also expressed in the majority of colonies. Growth factors also influenced neuronal maturation; the best neurite outgrowth was obtained from cells derived from bFGF-induced colonies cultured in the presence of EGF + bFGF. These data indicate the existence of neural precursor cells in the embryonic mesencephalon that respond differentially to growth factors. © 1995 Wiley-Liss, Inc.     

Effect of transforming growth factor-β1 and -β2 on Schwann cell proliferation on neurites

Mechanisms regulating Schwann cell proliferation during development are unclear. Schwann cell division is known to be driven by an unidentified mitogen present on the surface of axons, but it is not known whether other molecules play a role in regulating this proliferation. Transforming growth factor-beta (TGF-β) which is found in the developing peripheral nervous system (PNS) and is mitogenic for neuron-free Schwann cells in vitro could be involved. We have investigated the effects of TGF-β 1, TGF-β 2 and antibodies to TGF-β and TGF-β 2 on axon driven Schwann cell proliferation. Rat embryonic dorsal root ganglion neurons (DRG) neurons and Schwann cells from the sciatic nerve were isolated, purified and recombined in vitro. Confirming earlier reports by others, we observed that TGF-β 1 and TGF-β 2 added to the culture medium stimulated the proliferation of Schwann cells in the absence of neurons. However, when added to neuron-Schwann cell co-cultures, TGFβ caused a variable response ranging from no effect to moderate inhibition of Schwann cell proliferation in different experiments. A stimulation of Schwann cell proliferation by TGFβ was never observed in neuron-Schwann cell co-cultures. Antibodies to TGF-β and TGF-β 2 did not influence axon driven Schwann cell proliferation. To further determine the role of TGF-β in Schwann cell proliferation and myelination, we studied Schwann cell proliferation in cultures from mice in which the TGF-β 1 gene was delected by homologous recombination. Neuron-Schwann cell cultures from wild-type, heterozygous and homozygous mice were used. No differences were observed in either Schwann cell proliferation or myelination between cultures obtained from homozygous mutants and their heterozygous and wild-type controls. These findings suggest that TGF-β does not function as a part of the mitogenic mechanism presented by neurons to Schwann cells, but that the presence of active TGFβ in the cellular environment might regulate the degree of proliferation induced by neuronal contact. Copy 1995 Wiley-Liss, Inc.     

Interleukin-1β System (Ligand, Receptor Type I, Receptor Accessory Protein and Receptor Antagonist), TNF-α, TGF-β1 and Neuropeptide Y mRNAs in Specific Brain Regions During Bacterial LPS-Induced Anorexia

Bacterial lipopolysaccharide (LPS) or endotoxin induces neurological manifestations including anorexia. It is proposed that LPS-induced cytokine production is involved in the generation of neurological manifestations and in neuroinflammatory/immunological responses during Gram-negative infections. For example, LPS-induced effects can be blocked or ameliorated by the interleukin-1 receptor antagonist (IL-1Ra). Here, sensitive and specific RNase protection assays were used to investigate the effects of the intracerebroventricular (i.c.v.) administration of LPS on mRNA levels of interleukin-1β (IL-1β) system components, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and neuropeptide Y (NPY) in the cerebellum, hippocampus, and hypothalamus. The same brain region sample was analyzed with all of the antisense probes. The data show simultaneous local induction of multiple cytokine components messenger ribonucleic acids (mRNAs) within specific brain regions in anorectic rats responding to i.c.v. administered LPS (500 ng/rat). Interleukin-1β and IL-1Ra had a similar mRNA induction profile (hypothalamus > cerebellum > hippocampus). Interleukin-1 receptor type I (IL-1RI) mRNA also increased in all three brain regions examined, and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA was induced in the hypothalamus. Tumor necrosis factor-α mRNA levels increased in the hypothalamus > hippocampus > cerebellum. Levels of membrane bound IL-1R AcP, TGF-β1, and NPY mRNAs did not change significantly in any brain region. The results suggest that: (1) endogenous up-regulation of IL-1β and TNF-α in the hypothalamus contribute to LPS-induced anorexia; and (2) the ratio IL-1Ra/IL-1β, and IL-1β ↔ TNF-α interactions may have implications for Gram-negative infections associated with high levels of LPS in the brain-cerebrospinal fluid.