Turnbull, Andrew V., and Catherine L. Rivier. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action. Physiol. Rev. 79: 1–71, 1999. — Glucocorticoids a...

Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action

Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (−174G>C, −572G>C, and −597G>A) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (±95% CIs) were similar to those reported previously: −597A 0.36 (0.30 to 0.42), −572C 0.07 (0.04 to 0.10), and −174C 0.37 (0.31 to 0.43). The −174G>C and −597G>A genotypes were in strong allelic association (Δ=0.97, P P =0.03) in carriers of the −572C allele than in those of the −572GG genotype (355±67 versus 216±13 pg/mL, respectively) and in those with genotype −174CC compared with −174G allele carriers (287±31 versus 227±15 pg/mL, respectively; P =0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury.

Interleukin-6 Gene −174G>C and −572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery

Proinflammatory cytokines contribute to the development of inflammatory and neuropathic pain and hyperalgesia in manyin vivo models. The rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heat-evoked release of calcitonin gene-related peptide from nociceptorsin vitro. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any calcitonin gene-related peptide (CGRP) release at normal skin temperature of 32°C. However, the cytokines IL-1β, tumor necrosis factor (TNF)-α, and IL-6 but not IL-8 induced a pronounced and transient sensitization of the heat-evoked CGRP release from nociceptors in vitro. This heat sensitization was dose dependent, with EC50 for IL-1β of 2.7 ng/ml and for TNF-α of 3.1 ng/ml. The maximum IL-1β effect reached almost 600% of the heat-evoked release, and the maximum TNF-α effect induced a rise in CGRP release of 350%. In contrast to IL-1β and TNF-α, IL-6 did not induce heat sensitization when applied alone but was only effective in the presence of soluble IL-6 receptor. This suggests a constitutive expression of signaling receptors for TNF and IL-1β and the signal transduction molecule gp130 but not IL-6 receptor or IL-8 receptor. Furthermore, the acute cytokine signaling observed in the present study was independent of transcriptional pathways because sensitization occurred on short latency in vitroand under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Our results demonstrate that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy.

https://www.jneurosci.org/content/jneuro/20/16/6289.full.pdf

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

The present study was designed to determine the role of endogenous brain interleukin (IL)-1 in the anorexic response to lipopolysaccharide (LPS). Intraperitoneal administration of LPS (5–10 μg/mouse) induced a dramatic, but transient, decrease in food intake, associated with an enhanced expression of proinflammatory cytokine mRNA (IL-1β, IL-6, and tumor necrosis factor-α) in the hypothalamus. This dose of LPS also increased plasma levels of IL-1β. Intracerebroventricular pretreatment with IL-1 receptor antagonist (4 μg/mouse) attenuated LPS-induced depression of food intake and totally blocked the LPS-induced enhanced expression of proinflammatory cytokine mRNA measured in the hypothalamus 1 h after treatment. In contrast, LPS-induced increases in plasma levels of IL-1β were not altered. These findings indicate that endogenous brain IL-1 plays a pivotal role in the development of the hypothalamic cytokine response to a systemic inflammatory stimulus.

https://www.physiology.org/doi/pdf/10.1152/ajpregu.2000.279.1.R93

Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression

The immune and central nervous systems are functionally connectedand interacting. The concept that the immune signaling to the brainwhich induces fever during infection and inflammation is mediated bycirculating cytokines has been traditionally accepted. Administrationof bacterial lipopolysaccharide (LPS) induces the appearance of a so-termed ﬁcytokine cascadeﬂ in the circulation more or less concomi-tantly to the developing febrile response. Also, LPS-like fever can beinduced by systemic administration of key cytokines (IL-1s, TNF- a ,and others). However, anti-cytokine strategies against IL-1s or TNF-a along with systemic injections of LPS frequently lead to attenuationof the later stages of the febrile response but not of the initial phase offever, indicating that cytokines are rather involved in the maintenancethan in the early induction of fever. Within the last years experimentalevidence has accumulated indicating the existence of neural transportpathways of immune signals to the brain. Because subdiaphragmaticvagotomy prevents or attenuates fever in response to intraperitoneal orintravenous injections of LPS, a role for vagal afferent nerve fibers infever induction has been proposed. Also other sensory nerves mayparticipate in the manifestation of febrile responses under certainexperimental conditions. Thus, injection of a small dose of LPS intoan artificial subcutaneous chamber results in fever and formation ofcytokines within the inflamed tissue around the site of injection. Thisfebrile response can be blocked in part by injection of a local anes-thetic into the subcutaneous chamber, indicating a participation ofcutaneous afferent nerve signals in the manifestation of fever in thismodel. In conclusion, humoral signals and an inflammatory stimula-tion of afferent sensory nerves can participate in the generation andmaintenance of a febrile response.

/pdf/fever-induction-pathways-evidence-from-responses-to-systemic-2tpi1qn8oc.pdf

Fever induction pathways: evidence from responses to systemic or local cytokine formation.

Changes in concentrations of cytokines in plasma and in hypothalamic push-pull perfusates of guinea pigs were measured within the 1st hour after intramuscular injections of bacterial lipopolysaccharide (LPS; Escherichia coli, 20 micrograms/kg) or solvent (0.9% saline). In control animals injected with solvent, interleukin (IL)-1 and tumor necrosis factor alpha (TNF-alpha) were not detectable in plasma. Only IL-6 was present in picogram quantities. Within 45 min after injection of LPS, the concentrations of IL-1, TNF-alpha, and IL-6 increased in the plasma: by several orders of magnitude for TNF-alpha and about tenfold for IL-G. Picogram amounts of biologically active IL-1 were detected in plasma after injection of LPS. No steady state levels of systemic cytokines were reached during the experimental period. In hypothalamic perfusates of animals injected with the solvent, no IL-1 was detectable. TNF-alpha could be detected at higher concentrations than IL-6. IL-6 was detectable at tenfold lower concentrations than in the plasma. In animals injected with LPS, the hypothalamic concentration of IL-6 started to increase during the period 15-30 min and the concentrations of TNF-alpha during the period 30-45 min after LPS injection. The concentrations of IL-6 increased by 300-400% and did not exceed picogram values. No progressive increase of hypothalamic levels of these cytokines was observed during the time course of the experiment. The method used did not detect any changes in the amount of biologically active IL-1 in hypothalamic perfusates of LPS-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Jana Kamínková

Papers

Production of systemic and hypothalamic cytokines during the early phase of endotoxin fever.