Interleukin-1 β

Inflammation and tumor hypoxia are intimately linked and breast cancer provides a typical example of an inflammation-linked malignant disease. Indeed, breast cancer progression is actively supported by inflammatory components, including IL-1 beta, and by the hypoxia-inducible factor- (HIF-) 1 alpha In spite of many attempts where the role of either IL-1 beta or HIF-1 beta was evaluated, detailed mechanisms for their effects on breast cancer cell migration under hypoxia are still unclear. We here report that IL-1 beta increased MDAMB231 cell migration under hypoxic conditions along with HIF-1 alpha accumulation and upregulation of CXCR1, which is transcriptionally regulated by HIF-1 alpha, as well as an increased expression of CXCL8 and NF kappa B. In addition, IL-1 beta-induced cell migration in hypoxia was not affected when HIF-1 alpha was inhibited by either siRNA or Topotecan, well known for its inhibitory effect on HIF-1 alpha Of interest, HIF-1 alpha inhibition did not reduce NF kappa B and CXCL8 expression and the reduction of IL-1 beta-induced cell migration under hypoxia was achieved only by pharmacological inhibition of NF kappa B. Our findings indicate that inhibition of HIF-1 alpha does not prevent the migratory program activated by IL-1 beta in hypoxic MDAMB231 cells. They also suggest a potential compensatory role of NF kappa B/CXCL8 pathway in IL-1 beta-induced MDAMB231 cell migration in a hypoxic microenvironment

Mouse dendritic cells in the steady state: Hypoxia, autophagy, and stem cell factor

Dendritic cells (DCs) are innate immune cells with a central role in immunity and tolerance. Under steady-state, DCs are scattered in tissues as resting cells. Upon infection or injury, DCs get activated and acquire the full capacity to prime antigen-specific CD4(+) and CD8(+) T cells, thus bridging innate and adaptive immunity. By secreting different sets of cytokines and chemokines, DCs orchestrate diverse types of immune responses, from a classical proinflammatory to an alternative pro-repair one. DCs are highly heterogeneous, and physiological differences in tissue microenvironments greatly contribute to variations in DC phenotype. Oxygen tension is normally low in some lymphoid areas, including bone marrow (BM) hematopoietic niches; nevertheless, the possible impact of tissue hypoxia on DC physiology has been poorly investigated. We assessed whether DCs are hypoxic in BM and spleen, by staining for hypoxia-inducible-factor-1 alpha subunit (HIF-1 alpha), the master regulator of hypoxia-induced response, and pimonidazole (PIM), a hypoxic marker, and by flow cytometric analysis. Indeed, we observed that mouse DCs have a hypoxic phenotype in spleen and BM, and showed some remarkable differences between DC subsets. Notably, DCs expressing membrane c-kit, the receptor for stem cell factor (SCF), had a higher PIM median fluorescence intensity (MFI) than c-kit(-) DCs, both in the spleen and in the BM. To determine whether SCF (a.k.a. kit ligand) has a role in DC hypoxia, we evaluated molecular pathways activated by SCF in c-kit(+) BM-derived DCs cultured in hypoxic conditions. Gene expression microarrays and gene set enrichment analysis supported the hypothesis that SCF had an impact on hypoxia response and inhibited autophagy-related gene sets. Our results suggest that hypoxic response and autophagy, and their modulation by SCF, can play a role in DC homeostasis at the steady state, in agreement with our previous findings on SCF's role in DC survival

Hypoxia modulates cyclin and cytokine expression and inhibits peripheral mononuclear cell proliferation

Previously, we found that hypoxia can deeply affect the production of cytokines in human peripheral mononuclear cells (PBMC). Here, we demonstrated that the cycle progression of hypoxic PBMC, cultured in the presence or not of a specific T cell activator such as phytohaemagglutinin (PHA), was delayed when compared with aerobic cultures. This delay was accompanied by a decrease of the expression of specific cyclins associated to cell cycle progression phases. Ribonuclease Protection Assay (RPA) studies reveal a decrease in the expression of cyclin A and B in PHA-stimulated PBMC kept for 40 hr under hypoxic condition (2% O(2)), when compared with aerobic cultures (20% O(2)). In concomitance, a decrease of cyclin D2 expression was present after 16 hr of hypoxic treatment. However, the decrease was transient and disappeared after 40 hr of hypoxic treatment. Furthermore, cyclin C expression was not affected by hypoxia. Hypoxia-induced cyclin modulation was accompanied by an increased synthesis of interleukin (IL)-2 and IL-4, analyzed by ELISA. By evaluating these results, it appears that hypoxia induces a growth suppressive state in mitogen-activated PBMC by inhibiting the synthesis of mitotic cyclins A and B. However hypoxic PBMC maintain their viability and capability of producing stimulatory cytokines, after mitogen treatment. This should be important in local hypoxia, usually associated with necrotic areas, in inflammation, and infections, where T lymphocyte capability of producing stimulatory cytokines is desirable

Interleukin-1β Affects MDAMB231 Breast Cancer Cell Migration under Hypoxia: Role of HIF-1αand NFκB Transcription Factors

Inflammation and tumor hypoxia are intimately linked and breast cancer provides a typical example of an inflammation-linked malignant disease. Indeed, breast cancer progression is actively supported by inflammatory components, including IL-1 beta, and by the hypoxia-inducible factor- (HIF-) 1 alpha In spite of many attempts where the role of either IL-1 beta or HIF-1 beta was evaluated, detailed mechanisms for their effects on breast cancer cell migration under hypoxia are still unclear. We here report that IL-1 beta increased MDAMB231 cell migration under hypoxic conditions along with HIF-1 alpha accumulation and upregulation of CXCR1, which is transcriptionally regulated by HIF-1 alpha, as well as an increased expression of CXCL8 and NF kappa B. In addition, IL-1 beta-induced cell migration in hypoxia was not affected when HIF-1 alpha was inhibited by either siRNA or Topotecan, well known for its inhibitory effect on HIF-1 alpha Of interest, HIF-1 alpha inhibition did not reduce NF kappa B and CXCL8 expression and the reduction of IL-1 beta-induced cell migration under hypoxia was achieved only by pharmacological inhibition of NF kappa B. Our findings indicate that inhibition of HIF-1 alpha does not prevent the migratory program activated by IL-1 beta in hypoxic MDAMB231 cells. They also suggest a potential compensatory role of NF kappa B/CXCL8 pathway in IL-1 beta-induced MDAMB231 cell migration in a hypoxic microenvironment

Hypoxia enhances the antiviral activity of interferons

4sireservedWISH and Hep-2 cells were incubated in an environment with atmospheric oxygen (20% O2, approximately 140 mmHg partial pressure), and under hypoxic conditions (2% O2, approximately 14 mmHg). The oxygen tension greatly affected the metabolism of the cells and their response to interferon-alpha (IFN-alpha) and IFN-gamma. Under hypoxic conditions, the cytopathogenicity of vesicular stomatitis virus (VSV) was reduced by about 50%, and the antiviral effects of the interferons (IFNs) were increased, both in terms of VSV-induced cytopathic effect (CPE), and yields of infectious virus. Local hypoxia is a nonspecific host defense against virus infection. The present results suggest that one of the mechanisms is by potentiation of the effects of the IFN produced at the sites of virus replication.mixedNALDINI, A.; CARRARO, F.; FLEISCHMANN, W.R. JR; BOCCI, V.Naldini, A.; Carraro, F.; Fleischmann, W. R. JR; Bocci, V