Alexa Kabiersch

Cytokines as modulators of the hypothalamus-pituitary-adrenal axis

The hypothalamus-pituitary-adrenal (HPA) axis is stimulated during the course of certain immune, inflammatory and neoplastic processes. IL-1 is an important immunologically derived cytokine mediating the stimulation of this axis, although not the only one. We have compared the relative potencies of the cytokines IL-1, IL-6 and tumor necrosis factor (TNF), which share several biological actions, for stimulating ACTH and corticosterone output in freely-moving rats. Although all three cytokines can stimulate the HPA axis, IL-1 was the most potent. This effect of IL-1 was also present during the neonatal period, when the response of the HPA axis to acute stress is reduced in rodents. The results support the existence of an immune-HPA axis circuit. The biological and clinical relevance of this circuit is discussed.

Interleukin-1 induces changes in norepinephrine metabolism in the rat brain ☆

Interleukin-1 (IL-1) is a hormone that, apart from playing a key role in immune and inflammatory processes, can also affect mechanisms under brain control. To gain a better understanding of the action of this cytokine on the CNS, its effects on the contents of norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their main metabolites and precursors, were evaluated in different regions of the forebrain, brain stem, and spinal cord. Following administration of human recombinant IL-1 (beta form) to rats, a modest decrease in the content of NE was observed in the hypothalamus as well as in the dorsal posterior brain stem. However, the most relevant finding was that 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the main NE metabolite, and the relation MHPG/NE were increased in all the regions studied, revealing a stimulatory effect of IL-1 on NE metabolism in the CNS. This effect seems to be specific for NE since no comparable changes in the brain content of DA, 5-HT, or its metabolite, 5-hydroxyindole acetic acid, were detected after administration of the cytokine. However, tryptophan was significantly increased in all brain regions and in the cervical spinal cord. The capacity of IL-1 to affect the metabolism of NE, a neurotransmitter involved in the control of a variety of brain functions, provides further proof for the relevance of this cytokine in brain-immune interactions.

Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice

The regional distribution and inducibility of cytokines in the normal brain is still a matter of controversy. As an attempt to clarify this issue, we studied the constitutive and induced expression of interleukin (IL)‐1β, IL‐6, tumor necrosis factor (TNF)‐α, and interferon (IFN)‐γ mRNAs in the brain, pituitary, and spleen of mice using qualitative and semiquantitative reverse‐transcription polymerase chain reaction. The contribution of nonbrain cells to the cytokine transcripts detected was considered. With the exception of IFN‐γ mRNA, transcripts for the other cytokines were found to be constitutively present in the brain. Following i.p. injection of lipopolysaccharide (LPS) at a dose below those described to disrupt the blood‐brain barrier (BBB), cytokine mRNA expression was increased in the spleen, the pituitary, and the brain. In the brain, the onset of transcription varied from 45 min (IL‐1β, TNF‐α) to 4 hr (IFN‐γ), and the peak of mRNA accumulation was observed at different times depending on the cytokine and the brain region studied. IL‐1 and IL‐6 were highly expressed in the hypothalamus and hippocampus, while TNF‐α expression was more marked in the thalamus‐striatum. The cortex was the region in which cytokines were less inducible. The inducible expression of cytokine mRNAs in the brain was paralleled by stimulation of hypothalamus‐pituitary‐adrenal axis. These results show the capacity of brain cells to synthesize different cytokine mRNAs in vivo and define the kinetics of their expression in several brain areas and in the periphery in parallel to the activation of a neuroendocrine pathway by endotoxin. J. Neurosci. Res. 48:287–298, 1997.

Alterations in the Pituitary–Adrenal Axis of Adult Mice Following Neonatal Exposure to Interleukin-1

Interleukin-1 (IL-1), a cytokine mainly derived from activated cells of the macrophage lineage, can stimulate the hypothalamus-pituitary-adrenal (HPA) axis. Acute and long-lasting effects on the HPA axis were induced by the administration of low doses of IL-1 to mice during the first 5 days of life. In 5-day-old mice, corticosterone blood levels were markedly elevated 2 h following the last injection of IL-1. IL-1-treated mice grew normally. When studied during adulthood, however, these animals showed a reduction in morning values of corticosterone and the ACTH/corticosterone ratio was increased. Furthermore, an inverse correlation between ACTH and corticosterone levels in blood and between ACTH content in the pituitary gland and corticosterone levels was observed in IL-1-treated mice. Lower blood levels of corticosterone were not due to a reduced sensitivity of the adrenal glands, because these animals responded normally to exogenous ACTH. Another alteration observed in IL-1-exposed adult mice was a reduction in ACTH-like immunoreactivity in the pituitary gland following acute cold and restraint stress. It is concluded that exposure of mice to IL-1 early in life causes long-lasting alterations in the HPA axis. Spleen cells from adult mice treated with IL-1 at birth also developed a stronger response to allogeneic antigens than did cells from control mice. This observation indicates the relevance of immune-neuroendocrine interactions during development.

Involvement of noradrenergic nerves in the activation and clonal deletion of T cells stimulated by superantigen in vivo

Superantigens, like staphylococcal enterotoxin B (SEB), induce a strong proliferative response followed by clonal deletion of a substantial portion of defined Vbeta T cells. The remaining cells display in vitro anergy. We found that the immune response to SEB was paralleled by biphasic changes in the activity of the sympathetic nervous system. Furthermore, sympathetic denervation resulted in decreased SEB-induced cell proliferation and IL-2 production, and impeded the specific deletion of splenic CD4Vbeta8 cells observed in intact animals without affecting anergy. These studies provide the first evidence of an immunoregulatory cross-talk between sympathetic nerves and superantigen-activated immune cells.

Sympathetic Abnormalities during Autoimmune Processes

Abstract: The sympathetic nervous system is one of the major pathways involved in immune‐neuroendocrine interactions. Disturbances in these interactions are likely to have consequences during lymphoproliferative diseases. Work derived from our group as well as from several others led us to the hypothesis that the overstimulation of the immune system that characterizes this type of pathology results in decreased sympathetic nerve activity in lymphoid organs. To explore this possibility, we used as a model lpr/lpr mice, which develop a genetically determined autoimmune, lupus‐like lymphoproliferative disease. We show that 18‐week‐old female C57Bl/6J lpr/lpr mice, which do not show overt symptoms of the disease but already have increased IgM and IgG2a levels in the blood, have decreased noradrenaline (NA) concentration and content in the spleen, but not in the kidney, as compared to normal C57Bl/6J littermates. Lpr/lpr mice do not express normal Fas, and therefore apoptosis cannot be triggered through this receptor. The defects in sympathetic innervation in the spleen of lpr/lpr mice prompted us to evaluate whether NA could influence lymphoid cell mass by inducing apoptosis. We found that NA can directly induce apoptosis in normal lymphoid cells via β‐adrenergic receptors. From the reported results we propose that reduction in sympathetic nerve function in lpr/lpr mice contributes to aggravation of the disease and suggest that in addition to the incapacity to mount Fas‐mediated apoptosis, a second proapoptotic mechanism, namely, that triggered by NA, is defective in these animals because of reduced availability of the neurotransmitter.

The Role of Noradrenergic Nerves in the Development of the Lymphoproliferative Disease in Fas-Deficient, lpr/lpr Mice

Lpr/lpr mice develop a lymphoproliferative, autoimmune, lupus-like disease. These mice lack functional Fas (CD95) expression and are resistant to Fas ligand (CD178)-mediated apoptosis, a critical mechanism for the maintenance of peripheral tolerance. In this study, we show that noradrenaline (NA), the main sympathetic neurotransmitter, can induce apoptosis of lymphoid cells independently of functional Fas. Based on this finding, we used lpr/lpr mice as model to study the role of noradrenergic nerves in the expression of a lymphoproliferative disease. Early in ontogeny, the concentration of NA was significantly increased in the spleen of lpr/lpr mice, compared with normal littermates. However, splenic sympathetic innervation gradually declined as the disease progressed, and IgM blood levels and splenic NA concentration inversely correlated when the disease was overtly manifested. When the loss of noradrenergic fibers that occurred naturally during adult life in lpr/lpr mice was experimentally advanced by neonatal sympathectomy, the concentration of IgM and IgG2a in blood was markedly higher than that of control lpr/lpr mice, and the appearance of lymphadenopathy was accelerated. Furthermore, although neonatal denervation did not affect the life span of normal animals, it shortened significantly the survival time of lpr/lpr mice. These data show that, in addition to defects in the Fas pathway, an altered sympathetic innervation in lpr/lpr mice also contributes to the pathogenesis of the autoimmune disease, and strongly support the hypothesis that the sympathetic nervous system can modulate the expression of lymphoproliferative diseases.

Sympathetic Innervation Affects Superantigen-Induced Decrease in CD4Vβ8 Cells in the Spleen

Abstract: The stimulation by superantigens of T cells expressing an appropriate Vβ chain results in a strong proliferative response that is followed by a state of energy specific for the antigen used. This model was used to continue our studies on immunoregulatory host neuroendocrine responses. We have recently found that four days after administration of the superantigen staphylococcal enterotoxin B (SEB) into mice, that is, at an early stage of the anergic phase, the decrease in the percentage of splenic CD4Vβ8 was accompanied by a decrease in the splenic concentration of the sympathetic neurotransmitter noradrenaline (NA) as compared to vehicle‐injected mice. No comparable changes were detected in the kidney. At this point, blood levels of NA, adrenaline, and corticosterone were comparable in SEB‐ and vehicle‐injected mice. We have also found that the decrease in splenic CD4Vβ8 cells was not observed in animals that had been chemically sympathectomized prior to the administration of the superantigen. These results indicate that the sympathetic response induced by SEB may have immunoregulatory implications.