IL-10 as a mediator in the HPA axis and brain

Smith, Eric M.; Cadet, Patrick; Stefano, George B.; Opp, Mark R.; Hughes, Thomas K.

doi:10.1016/s0165-5728(99)00206-4

Cited by 110 publications

(73 citation statements)

References 63 publications

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“…The synthesis of IL-10 is increased in mycobacterial (42) and influenza (43) infections, and at least some of its anti-inflammatory properties in vivo result from activation of the hypothalamic-pituitary adrenal axis (44). Progenitor CD34 ϩ cells that develop into myeloid cells and mature macrophages express IL-10Rs, so we were not surprised to find a 110-kDa IL-10R1 on myeloid progenitor cells.…”

Section: Discussionmentioning

confidence: 91%

IL-10 Inhibits Apoptosis of Promyeloid Cells by Activating Insulin Receptor Substrate-2 and Phosphatidylinositol 3′-Kinase

Zhou

Broussard

Strle

et al. 2001

The Journal of Immunology

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IL-10 is well known to be a potent inhibitor of the synthesis of proinflammatory cytokines, but noninflammatory hemopoietic cells also express IL-10Rs. Here we show that IL-10 directly affects progenitor myeloid cells by protecting them from death following the removal of growth factors. Murine factor-dependent cell progenitors cultured in the absence of growth factors were 43 ± 1% apoptotic after 12 h. Addition of IL-10 at a concentration as low as 100 pg/ml significantly reduced the apoptotic population to 32 ± 3%. At 10 ng/ml, IL-10 caused a 4-fold reduction in the apoptotic population (11 ± 1%). The anti-apoptotic activity of IL-10 was significantly inhibited with a neutralizing IL-10R Ab. Factor-dependent cell progenitor promyeloid cells expressed functional IL-10Rs, as assessed by precipitation of a 110-kDa protein with an Ab to the IL-10R and by the ability of IL-10 to activate Jak1 and Tyk2 and to phosphorylate tyrosine 705 on Stat-3. IL-10 increased tyrosyl phosphorylation of insulin receptor substrate-2 and stimulated the enzymatic activity of both phosphatidylinositol 3′-kinase and Akt. The anti-apoptotic activity of IL-10 was blocked by inhibition of phosphatidylinositol 3′-kinase. Wortmannin and LY294002 also totally inhibited activation of extracellular signal-related kinase (ERK)1/2 by IL-10. Direct inhibition of ERK1/2 with the mitogen-activated protein kinase/ERK kinase inhibitor PD98059 partially, but significantly, impaired the anti-apoptotic activity of IL-10. These data establish that activation of the IL-10R promotes survival of progenitor myeloid cells. This survival-promoting activity is totally due to IL-10 stimulating the insulin receptor substrate-2/PI 3-kinase/Akt pathway, which increases the anti-apoptotic activity of ERK1/2.

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Section: Discussionmentioning

confidence: 91%

IL-10 Inhibits Apoptosis of Promyeloid Cells by Activating Insulin Receptor Substrate-2 and Phosphatidylinositol 3′-Kinase

Zhou

Broussard

Strle

et al. 2001

The Journal of Immunology

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“…Therefore, it is not surprising that after 6 h of cLPS stimulation, all plasma cytokines were elevated in WT mice, indicating a competent inflammatory response. In addition, IL-10, which, aside from its recognized role in immunity also acts as an endogenous regulator of the HPA axis (42), was increased after a cLPS stimulus in WT animals. In contrast, pLPS had no effect in WT mice, indicating that TLR-2 signaling contributes to the observed activation of cytokines.…”

Section: Discussionmentioning

confidence: 96%

Toll-like receptor 4 plays a crucial role in the immune–adrenal response to systemic inflammatory response syndrome

Zacharowski

Zacharowski²,

Koch³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

128

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Sepsis and septic shock are leading killers in the noncoronary intensive care unit, and they remain worldwide health concerns. The initial host defense against bacterial infections involves Tolllike receptors (TLRs), which detect and respond to microbial ligands. In addition, a coordinated response of the adrenal and immune systems is crucial for survival during severe inflammation. Previously, we demonstrated a link between the innate immune system and the endocrine stress response involving TLR-2. Like TLR-2, TLR-4 is also expressed in human and mouse adrenals. In the present work, by using a low dose of LPS to mimic systemic inflammatory response syndrome, we have revealed marked cellular alterations in adrenocortical tissue and an impaired adrenal corticosterone response in TLR-4 ؊/؊ mice. Our findings demonstrate that TLR-4 is a key mediator in the crosstalks between the innate immune system and the endocrine stress response. Furthermore, TLR polymorphisms could contribute to the underlying mechanisms of impaired adrenal stress response in patients with bacterial sepsis.lipopolysaccharide ͉ stress axis ͉ sepsis ͉ corticoids ͉ mice

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“…IL1β increases the firing rate of a subpopulation of anterior hypothalamic, sleep-active neurons while it suppresses the firing rate in most of the wake-active neurons in this region (Alam et al, 2004). Other cytokines, such as interleukin-6 and interleukin-10 ( Alberti et al, 2003;Hogan et al, 2003;Toth and Opp, 2001;Shearer et al, 2001;Smith et al, 1999) as well as NGF (Kapas et al, 1996) and BDNF , also affect sleep and interact with TNFα and IL1β. Current results have bearing on these findings to the extent that we demonstrate that both IL1 and TNF have broad-ranging actions on other cytokines; each with distinct time courses of mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Cytokine mRNA induction by interleukin-1β or tumor necrosis factor α in vitro and in vivo

Taishi

Churchill

et al. 2008

Brain Research

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Hypothalamic and cortical mRNA levels for cytokines such as interleukin-1α (IL1α), tumor necrosis factor alpha (TNFα), nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are impacted by systemic treatments of IL1β and TNFα To investigate the time course of the effects of IL1β and TNFα on hypothalamic and cortical cytokine gene expression, we measured mRNA levels for IL1β, TNFα, interleukin-6 (IL-6), interleukin-10 (IL-10), IL1 receptor 1, BDNF, NGF, and glutamate decarboxylase-67 in vitro using hypothalamic and cortical primary cultures. IL1β and TNFα mRNA levels increased significantly in a dose-dependent fashion after exposure to either IL1β or TNFα. IL1β increased IL1β mRNA in both the hypothalamic and cortical cultures after 2-6 h while TNFα mRNA increased significantly within 30 min and continued to rise up to 2-6 h. Most of the other mRNAs showed significant changes independent of dose in vitro. In vivo, intracerebroventricular (icv) injection of IL1β or TNFα also significantly increased IL1β, TNFα and IL6 mRNA levels in the hypothalamus and cortex. IL1β icv, but not TNFα increased NGF mRNA levels in both these areas. Results support the hypothesis that centrally active doses of IL1β and TNFα enhance their own mRNA levels as well as affect mRNA levels for other neuronal growth factors.

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IL-10 as a mediator in the HPA axis and brain

Cited by 110 publications

References 63 publications

IL-10 Inhibits Apoptosis of Promyeloid Cells by Activating Insulin Receptor Substrate-2 and Phosphatidylinositol 3′-Kinase

IL-10 Inhibits Apoptosis of Promyeloid Cells by Activating Insulin Receptor Substrate-2 and Phosphatidylinositol 3′-Kinase

Toll-like receptor 4 plays a crucial role in the immune–adrenal response to systemic inflammatory response syndrome

Cytokine mRNA induction by interleukin-1β or tumor necrosis factor α in vitro and in vivo

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