Interleukin-8 production from human somatotroph adenoma cells is stimulated by interleukin-1β and inhibited by growth hormone releasing hormone and somatostatin

Vindeløv, Signe Diness; Hartoft‐Nielsen, Marie‐Louise; Rasmussen, Åse Krogh; Bendtzen, Klaus; Kosteljanetz, Michael; Andersson, Anna‐Maria; Feldt‐Rasmussen, Ulla

doi:10.1016/j.ghir.2011.03.005

Cited by 14 publications

(9 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PitNETs with more macrophages were associated with higher levels of IL-8, a chemokine that influences several oncogenic pathways [1, 86]. IL-8 mRNA was previously found in PitNETs, although different detection methods provided a wide range of expression levels [23, 76, 84]. We also identified other chemokines potentially relevant in PitNETs, namely CXCL10, CCL22, CXCL1 and CX3CL1.…”

Section: Discussionmentioning

confidence: 67%

“…Studying the TME may provide novel insights into PitNET biology and may lead to development of novel therapies, such as the successful ipilimumab and nivolumab combined treatment in a patient with an ACTH-secreting pituitary carcinoma [35]. Previous studies have assessed CXCL12 [8, 19, 33, 48, 58, 88, 91], IL-8 [23, 76, 84] and immune cells [6, 37, 38, 52, 85] in PitNETs. However, the crosstalk between the cytokine network and immune cells in determining the PitNET phenotype has not been previously comprehensively explored.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Marques

Barry

Carlsen³

et al. 2019

acta neuropathol commun

105

View full text Add to dashboard Cite

Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n = 5). In vitro tumour–macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (p = 0.005), but fewer neutrophils (p = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with “deleterious immune phenotype” (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p = 0.015) and area (p < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.

show abstract

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Marques

Barry

Carlsen³

et al. 2019

acta neuropathol commun

105

View full text Add to dashboard Cite

show abstract

“…Somatostatin, a significant peptide for inhibiting cell proli fe ration and differentiation, is able to retard the growth of various types of cells by blocking the synthesis and/or secretion of numerous key cytokines and hormones (8)(9)(10)(11)(12). At a low dose, somatostatin may exert antiproliferative and proapoptotic activities on activated HSCs.…”

Section: Introductionmentioning

confidence: 99%

The mechanism through which octreotide inhibits hepatic stellate cell activity

Wang

Song

et al. 2013

Molecular Medicine Reports

View full text Add to dashboard Cite

Hepatic stellate cells (HSCs) are important in the development of liver fibrosis and in the pathogenesis of portal hypertension. Octreotide, an analogue of somatostatin, has been demonstrated to effectively treat fibrosis and portal hypertension; however, its relative mechanism in HSCs remains unknown. LX‑2, the immortalized HSC line, was used to study the mechanism whereby octreotide functions at different concentrations. Real‑time polymerase chain reaction (PCR) and western blot analysis were used to analyze the expression of fibrosis markers and transcription factors following treatment with octreotide. Soluble secreted endothelin‑1 (ET‑1), collagen I and vascular endothelial growth factor (VEGF) were assessed in the supernatants of cultured cells by enzyme-linked immunosorbent assay (ELISA). In the present study, it was shown that octreotide was able to inhibit the proliferative ability of the LX‑2 cells and decrease the expression of transforming growth factor β (TGF‑β), α‑smooth muscle actin (α‑SMA) and smad‑4a. The transcription factors, including c‑Jun and sp‑1, were downregulated in a dose‑dependent manner following treatment with octreotide. The levels of ET‑1 and collagen I in the supernatant decreased significantly in contrast with the normal levels, whereas the levels of VEGF in the LX‑2 cells and the supernatant increased at a high octreotide concentration (10‑5 nM). Octreotide may exert its effects on ET‑1 or other targeting genes in HSCs through the downregulation of c‑Jun and specificity protein 1 (sp‑1), and the increased levels of VEGF may be the reason for the side effects observed at high concentrations of octreotide.

show abstract

“…Somatostatin controls hormone secretion and proliferation in normal and neoplastic pituitary and reduced IL-6 and IL-8 in human somatotropinoma cultures (Thiele et al 2003, Vindelov et al 2011). Somatostatin's inhibitory effect on IL-6 secretion was also shown in nonpituitary cells (Grimaldi et al 1997, Andoh et al 2002 Endocrine-Related Cancer Spangelo et al 2004).…”

Section: Figurementioning

confidence: 99%

Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness

Marques

Barry

Carlsen³

et al. 2019

Endocrine-Related Cancer

View full text Add to dashboard Cite

Tumour-associated fibroblasts (TAFs) are key elements of the tumour microenvironment, but their role in pituitary neuroendocrine tumours (PitNETs) has been little explored. We hypothesised that TAF-derived cytokines may play a role in tumour aggressiveness and that their release can be inhibited by somatostatin analogues. TAFs were isolated and cultured from 16 PitNETs (11 clinically non-functioning tumours and 5 somatotropinomas). The fibroblast secretome was assessed with a 42-plex cytokine array before and after multiligand somatostatin receptor agonist pasireotide treatment. Angiogenesis and epithelial-to-mesenchymal transition pathway assessment included CD31, E-cadherin and ZEB1 expression. GH3 cells treated with TAF- or skin fibroblast-conditioned medium were assessed for migration, invasion and cell morphology changes. PitNET TAFs secreted significant amounts of cytokines including CCL2, CCL11, VEGF-A, CCL22, IL-6, FGF-2 and IL-8. TAFs from PitNETs with cavernous sinus invasion secreted higher IL-6 levels compared to fibroblasts from non-invasive tumours (P = 0.027). Higher CCL2 release from TAFs correlated with more capillaries (r = 0.672, P = 0.004), and TAFs from PitNETs with a higher Ki-67 tended to secrete more CCL2 (P = 0.058). SST1 is the predominant somatostatin receptor in TAFs, and pasireotide decreased TAF-derived IL-6 by 80% (P < 0.001) and CCL2 by 35% (P = 0.038). GH3 cells treated with TAF-conditioned medium showed increased migration and invasion compared to cells treated with skin fibroblast-conditioned medium, with morphological and E-cadherin and ZEB1 expression changes suggesting epithelial-to-mesenchymal transition. TAF-derived cytokines may increase PitNET aggressiveness, alter angiogenesis and induce epithelial-to-mesenchymal transition changes. Pasireotide’s inhibitory effect on TAF-derived cytokines suggest that this effect may play a role in its anti-tumour effects.

show abstract

Interleukin-8 production from human somatotroph adenoma cells is stimulated by interleukin-1β and inhibited by growth hormone releasing hormone and somatostatin

Cited by 14 publications

References 73 publications

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

The mechanism through which octreotide inhibits hepatic stellate cell activity

Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness

Contact Info

Product

Resources

About