Acute elevation of interleukin 6 and matrix metalloproteinase 9 during the onset of pituitary apoplexy in Cushing’s disease

Abstract

Purpose

Pituitary apoplexy is a rare endocrine emergency. The purpose of this study is to characterize physiological changes involved in pituitary apoplexy, especially during the acute phase.

Methods

A Cushing’s disease patient experienced corticotroph releasing hormone (CRH)-induced pituitary apoplexy during inferior petrosal sinus sampling (IPSS). The IPSS blood samples from the Cushing’s disease patient were retrospectively analyzed for cytokine markers. For comparison, we also analyzed cytokine markers in blood samples from two pituitary ACTH-secreting microadenoma patients and one patient with an ectopic ACTH-secreting tumor.

Results

Acute elevation of interleukin 6 (IL-6) and matrix metalloproteinase 9 (MMP9) was observed in the IPSS blood sample on the apoplectic hemorrhagic site of the tumor. In contrast, such a change was not observed in the blood samples from the contralateral side of the apoplexy patient and in other IPSS samples from two non-apoplexy Cushing’s disease patient and a patient with ectopic Cushing’s syndrome.

Conclusion

IL-6 and MMP9 may be involved in the acute process of pituitary apoplexy in Cushing’s disease.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Briet C et al (2015) Pituitary apoplexy. Endocr Rev 36(6):622–645

    Article  Google Scholar 

  2. 2.

    Baldeweg SE et al (2016) Society for Endocrinology Endocrine Emergency Guidance: emergency management of pituitary apoplexy in adult patients. Endocr Connect 5(5):G12–G15

    Article  Google Scholar 

  3. 3.

    Capatina C et al (2015) Management of endocrine disease: pituitary tumour apoplexy. Eur J Endocrinol 172(5):R179–R190

    CAS  Article  Google Scholar 

  4. 4.

    Zhang F et al (2009) Manifestation, management and outcome of subclinical pituitary adenoma apoplexy. J Clin Neurosci 16(10):1273–1275

    Article  Google Scholar 

  5. 5.

    Otsuka F et al (1998) Pituitary apoplexy induced by a combined anterior pituitary test: case report and literature review. Endocr J 45(3):393–398

    CAS  Article  Google Scholar 

  6. 6.

    Kaltsas GA et al (1999) A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing’s disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 84(2):487–492

    CAS  PubMed  Google Scholar 

  7. 7.

    Jehle S et al (2008) Selective use of bilateral inferior petrosal sinus sampling in patients with adrenocorticotropin-dependent Cushing’s syndrome prior to transsphenoidal surgery. J Clin Endocrinol Metab 93(12):4624–4632

    CAS  Article  Google Scholar 

  8. 8.

    Gupta P, Dutta P (2018) Landscape of molecular events in pituitary apoplexy. Front Endocrinol 9:107

    Article  Google Scholar 

  9. 9.

    Xiao Z et al (2011) Hypoxia induces hemorrhagic transformation in pituitary adenomas via the HIF-1α signaling pathway. Oncol Rep 26(6):1457–1464

    CAS  PubMed  Google Scholar 

  10. 10.

    Xiao Z et al (2011) TNF-α-induced VEGF and MMP-9 expression promotes hemorrhagic transformation in pituitary adenomas. Int J Mol Sci 12(6):4165–4179

    CAS  Article  Google Scholar 

  11. 11.

    Ishikawa H et al (2001) Human pituitary tumor-transforming gene induces angiogenesis. J Clin Endocrinol Metab 86(2):867–874

    CAS  PubMed  Google Scholar 

  12. 12.

    Jayaraman T et al (2008) TNF-alpha-mediated inflammation in cerebral aneurysms: a potential link to growth and rupture. Vasc Health Risk Manag 4(4):805–817

    CAS  Article  Google Scholar 

  13. 13.

    Kim K, Yoshida D, Teramoto A (2005) Expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in pituitary adenomas. Endocr Pathol 16(2):115–121

    CAS  Article  Google Scholar 

  14. 14.

    Cristina C, Luque GM (2014) Angiogenesis in pituitary adenomas: human studies and new mutant mouse models. Int J Endocrinol 2014:608497

    Article  Google Scholar 

  15. 15.

    Jarzembowski J, Lloyd R, McKeever P (2007) Type IV collagen immunostaining is a simple, reliable diagnostic tool for distinguishing between adenomatous and normal pituitary glands. Arch Pathol Lab Med 131(6):931–935

    CAS  Article  Google Scholar 

  16. 16.

    Kawamoto H et al (1996) Type IV collagenase activity and cavernous sinus invasion in human pituitary adenomas. Acta Neurochir (Wien) 138(4):390–395

    CAS  Article  Google Scholar 

  17. 17.

    Lambertsen KL, Biber K, Finsen B (2012) Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab 32(9):1677–1698

    CAS  Article  Google Scholar 

  18. 18.

    Tsuge M et al (2010) Increase of tumor necrosis factor-alpha in the blood induces early activation of matrix metalloproteinase-9 in the brain. Microbiol Immunol 54(7):417–424

    CAS  PubMed  Google Scholar 

  19. 19.

    Spinale FG, Villarreal F (2014) Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochem Pharmacol 90(1):7–15

    CAS  Article  Google Scholar 

  20. 20.

    Zhang X, Shen YH, LeMaire SA (2009) Thoracic aortic dissection: are matrix metalloproteinases involved? Vascular 17(3):147–157

    Article  Google Scholar 

  21. 21.

    Ryuto M et al (1996) Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. J Biol Chem 271(45):28220–28228

    CAS  Article  Google Scholar 

  22. 22.

    Li G et al (2014) The relationship between serum hypoxia-inducible factor 1α and coronary artery calcification in asymptomatic type 2 diabetic patients. Cardiovasc Diabetol 13:52–52

    Article  Google Scholar 

  23. 23.

    Shao Y et al (2016) Levels of serum 25(OH)VD3, HIF-1α, VEGF, vWf, and IGF-1 and their correlation in type 2 diabetes patients with different urine albumin creatinine ratio. J Diabetes Res 2016:1925424

    Article  Google Scholar 

  24. 24.

    Rong B et al (2018) Correlation of serum levels of HIF-1α and IL-19 with the disease progression of COPD: a retrospective study. Int J Chron Obstruct Pulmon Dis 13:3791–3803

    CAS  Article  Google Scholar 

  25. 25.

    He J et al (2016) The relationship between the preoperative plasma level of HIF-1α and clinic pathological features, prognosis in non-small cell lung cancer. Sci Rep 6:20586

    CAS  Article  Google Scholar 

  26. 26.

    Loriaux DL (2017) Diagnosis and differential diagnosis of Cushing’s syndrome. N Engl J Med 376(15):1451–1459

    CAS  Article  Google Scholar 

  27. 27.

    Gandhi CD et al (2008) Neurologic complications of inferior petrosal sinus sampling. Am J Neuroradiol 29(4):760–765

    CAS  Article  Google Scholar 

  28. 28.

    Elshal MF, McCoy JP (2006) Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods (San Diego, Calif.) 38(4):317–323

    CAS  Article  Google Scholar 

  29. 29.

    Rotman-Pikielny P, Patronas N, Papanicolaou DA (2003) Pituitary apoplexy induced by corticotrophin-releasing hormone in a patient with Cushing’s disease. Clin Endocrinol 58(5):545–549

    Article  Google Scholar 

  30. 30.

    Chen R et al (1993) Expression cloning of a human corticotropin-releasing-factor receptor. Proc Natl Acad Sci USA 90(19):8967–8971

    CAS  Article  Google Scholar 

  31. 31.

    Kameda H et al (2019) Proton sensitivity of corticotropin-releasing hormone receptor 1 signaling to proopiomelanocortin in male mice. Endocrinology 160(2):276–291

    CAS  Article  Google Scholar 

  32. 32.

    Venihaki M et al (2001) Corticotropin-releasing hormone regulates IL-6 expression during inflammation. J Clin Invest 108(8):1159–1166

    CAS  Article  Google Scholar 

  33. 33.

    Turnbull AV et al (1999) CRF type I receptor-deficient mice exhibit a pronounced pituitary-adrenal response to local inflammation. Endocrinology 140(2):1013–1017

    CAS  Article  Google Scholar 

  34. 34.

    Kothari P et al (2014) IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages. J Immunol (Baltimore, Md.: 1950) 192(1):349–357

    CAS  Article  Google Scholar 

  35. 35.

    Kanbe N et al (1999) Human mast cells produce matrix metalloproteinase 9. Eur J Immunol 29(8):2645–2649

    CAS  Article  Google Scholar 

  36. 36.

    Taniguchi-Ponciano K et al (2020) Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors. Sci Rep 10(1):19373

    CAS  Article  Google Scholar 

  37. 37.

    Turner HE et al (2000) Role of matrix metalloproteinase 9 in pituitary tumor behavior. J Clin Endocrinol Metab 85(8):2931–2935

    CAS  Article  Google Scholar 

  38. 38.

    Paoletta A et al (2011) Intrapituitary cytokines in Cushing’s disease: do they play a role? Pituitary 14(3):236–241

    CAS  Article  Google Scholar 

  39. 39.

    Watanobe H et al (1998) Measurement of cytokines in the cavernous sinus plasma from patients with Cushing’s disease. Neuropeptides 32(2):119–123

    CAS  Article  Google Scholar 

  40. 40.

    Sothern RB et al (1995) Circadian characteristics of circulating interleukin-6 in men. J Allergy Clin Immunol 95(5 Pt 1):1029–1035

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This study is supported by grants from the University of Minnesota (UMF0011528 to TA, AHC Grant-in-Aid 212588 to TA) and a grant from the NIH (R01AR064195 to YK). We are grateful to Dr. Yasumasa Iwasaki for critical reading, to Cailin McMahon and Mathew Pappas for editorial assistance, to Justin Wang for his excellent technical assistance and to Michael Ehrhardt at the Cytokine reference laboratory for blood sample assays.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Takako Araki.

Ethics declarations

Conflict of interest

The authors have no multiplicity of interest to disclose.

Ethical approval

Study protocols were approved by the University of Minnesota Institutional Review Board (protocol #00005168). Informed consent was obtained from patients over 18 years of age, who were diagnosed with Cushing’s syndrome and underwent the IPSS procedure.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (TIF 5393 kb)

Supplementary file2 (DOCX 12 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Araki, T., Sangtian, J., Ruanpeng, D. et al. Acute elevation of interleukin 6 and matrix metalloproteinase 9 during the onset of pituitary apoplexy in Cushing’s disease. Pituitary (2021). https://doi.org/10.1007/s11102-021-01157-0

Download citation

Keywords

  • Pituitary apoplexy
  • IL-6
  • MMP9
  • Cushing's disease
  • CRH