Turk J Immunol. 2013; 1(3): 68-73 | DOI: 10.5606/tji.2013.268

Interleukin-12 and Protamine Inhibit Angiogenesis and Growth of C6 Rat Glioma: Synergistic Effects and Role of Th2 Cells

Akif Turna¹, Bayram Kýran², Engin Ozar³, Hande Turna⁴, Cem Ahmet Mercan⁵, Nur Büyükpýnarbaþýlý⁶, Ayhan Bilir⁷, Günnur Deniz^8
1Department of Thoracic Surgery, Ýstanbul University, Cerrahpaþa Medical Faculty, Ýstanbul, Turkey
²Department of Biology, Medical Faculty of Kastamonu University, Kastamonu, Turkey
³Department of Neurosurgery, Bakýrköy Prof. Dr. Mazhar Osman Psychiatric and Neurological Diseases Training and Research Hospital, Ýstanbul, Turkey
⁴Department of Medical Oncology, Ýstanbul University, Cerrahpasa Medical Faculty, Ýstanbul, Turkey
⁵Department of Computational Science, Ýstanbul Technical University, Ýstanbul, Turkey
⁶Department of Pathology, Medical Faculty of Bezmialem Vakýf Gureba University, Ýstanbul, Turkey
⁷Department of Histology and Embryology, Ýstanbul University, Ýstanbul Faculty of Medicine, Ýstanbul, Turkey
⁸Department of Immunology, Ýstanbul University, Institute for Experimental

Objectives: This study aims to investigate the anti-tumoral, anti-angiogenic and immunologic effects of interleukin-12 (IL-12) in combination with protamine in intracranially inoculated rat C6 glioma model. Material and methods: A 12-week-old 60 female Sprague-Dawley rats with a mean weight of 208±19 g were divided into six groups: C6 glioma cells were inoculated in group A; tumor in combination with recombinant IL-12 (rIL-12) 10 ng were inoculated intracranially in group B; rIL-12 10 ng intracranially with protamine 60 mg/kg subcutaneously were given to group C; protamine subcutaneously was given to group D; vehicle was given subcutaneously to group E; rIL-12 10 ng was subcutaneously given with protamine and tumor was inoculated in group F. Results: Intracranial rIL-12 and protamine exerted both anti-tumoral and anti-angiogenic effects (p=0.001). Intracranial rIL-12 administration significantly diminished peripheral blood Th2 cell ratio (p=0.03) and improved survival of the rats (p=0.001). Protamine monotherapy or in combination with IL-12 showed no immunologic alteration in T helper cell population. Conclusion: Recombinant IL-12 and protamine are effective against intracranially inoculated glioma, improve survival significantly as monotherapy or combination therapy and alter T helper cell cytokine secretion profile in favor of Th2 in rats.

Keywords: Angiogenesis; C6; glioma; interleukin-12; lymphocyte; protamine; Th1 cell; Th2 cell.

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Interleukin-12 ve Protamin C6 Sýçan Gliomanýn Anjiyogenezini ve Büyümesini Ýnhibe Eder: Sinerjik Etkiler ve Th2 Hücrelerinin Rolü

Akif Turna¹, Bayram Kýran², Engin Ozar³, Hande Turna⁴, Cem Ahmet Mercan⁵, Nur Büyükpýnarbaþýlý⁶, Ayhan Bilir⁷, Günnur Deniz^8
1Department of Thoracic Surgery, Ýstanbul University, Cerrahpaþa Medical Faculty, Ýstanbul, Turkey
²Department of Biology, Medical Faculty of Kastamonu University, Kastamonu, Turkey
³Department of Neurosurgery, Bakýrköy Prof. Dr. Mazhar Osman Psychiatric and Neurological Diseases Training and Research Hospital, Ýstanbul, Turkey
⁴Department of Medical Oncology, Ýstanbul University, Cerrahpasa Medical Faculty, Ýstanbul, Turkey
⁵Department of Computational Science, Ýstanbul Technical University, Ýstanbul, Turkey
⁶Department of Pathology, Medical Faculty of Bezmialem Vakýf Gureba University, Ýstanbul, Turkey
⁷Department of Histology and Embryology, Ýstanbul University, Ýstanbul Faculty of Medicine, Ýstanbul, Turkey
⁸Department of Immunology, Ýstanbul University, Institute for Experimental

Amaç: B u ç alýþmada, i nterlökin-12 ( IL-12) v e p rotaminin b irlikte k ullanýmýnýn i ntrakraniyal o larak inoküle edilmiþ C6 glioma sýçan modelinde antitümöral, antianjiyojenik ve immünolojik etileri araþtýrýldý. Gereç ve yöntemler: Altmýþ adet 12 haftalýk ortalama 208±19 g aðýrlýðýnda Sprague-Dawley cinsi diþi sýçan altý gruba ayrýldý: Grup A’da yalnýzca C6 glioma hücreleri inoküle edildi; grup B’ye tümör ile birlikte intrakraniyal olarak 10 ng rekombinant IL-12 (rIL-12) verildi; grup C’ye intrakraniyal olarak 10 ng rIL-12 ile birlikte subkutan 60 mg/kg protamin verildi; grup D’ye yalnýzca subkutan protamin verildi; grup E’ye subkutan olarak yalnýzca taþýyýcý verilirdi; grup F’ye tümör ile birlikte subkutan 10 ng rIL-12 ve protamin verildi. Bulgular: Ýntrakraniyal olarak uygulanan rIL-12 ve protamin, hem anti-tümöral hem de anti-anjiyogenik etkiler gösterdi (p=0.001). Ýntrakraniyal rIL-12 uygulamasý, periferik kandaki Th2 hücrelerinin oranýný düþürdü (p=0.03) ve sýçanlarýn saðkalýmlarýný iyileþtirdi (p=0.001). Protamin, IL-12’ye ek olarak ya da tek baþýna T yardýmcý hücre popülasyonunda ölçtüðümüz immünolojik bir deðiþiklik yaratmadý. Sonuç: Rekombinant IL-12 ve protamin sýçanlarda intrakraniyal olarak inoküle edilen gliomaya karþýn etkin olmakta, saðkalýmý tek baþýna veya birlikte uygulanmasý ile anlamlý bir iyileþme saðlamakta ve periferik kandaki T yardýmcý hücrelerinin sitokin salgýlama profilini Th2 aleyhine deðiþtirmektedir.

Anahtar Kelimeler: Anjiyogenez; C6; glioma; interlökin-12; lenfosit; protamin; Th1 hücre; Th2 hücre.

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