Interleukin-1 beta is an irradiation-induced stromal growth factor Alexey E. Bigildeev ⇑ , Oxana A. Zhironkina, Oxana N. Lubkova, Nina J. Drize Laboratory Physiology of Hematopoiesis, Hematological Research Center, Ministry of Health, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation article info Article history: Received 6 March 2013 Received in revised form 14 June 2013 Accepted 2 July 2013 Available online xxxx Keywords: Interleukin 1 beta Gamma irradiation Growth factor for hematopoietic stromal microenvironment Hematopoietic ectopic foci Stromal microenvironment abstract Gamma irradiation of tissues and organs leads to many pathological consequences due to the formation of reactive oxygen species, DNA damage and the subsequent massive death of cells. The therapeutic use of gamma irradiation in the treatment of cancer is based on its penetrating power and damaging effects on tumor cells. Other effects from the irradiation are unnoticeable in comparison. Moreover, the long-term consequences of gamma irradiation are still poorly understood. When a donor bone marrow plug is implanted under the renal capsule of a syngeneic animal, a hematopoietic ectopic focus is formed. The size of the focus is increased in mice that received irradiation compared to non-irradiated ones, regardless of the amount of time between irradiation and bone marrow plug implantation. Long-term repetitive injec- tions of blood serum from irradiated mice given to syngeneic non-irradiated recipients of bone marrow plugs also lead to the formation of enlarged foci. Hence, the blood of irradiated animals must contain an activity that induces the growth of a hematopoietic microenvironment. It was previously shown that the bones of irradiated animals secrete a growth factor required to create stromal microenvironments. The identity of this factor has, until now, been difficult to obtain. We demonstrated that interleukin 1 beta (IL-1) stimulates the growth of murine bone marrow stromal cells in vitro and in vivo. It was shown that the expression of the Il1b gene and the secretion of its product, IL-1, were activated in bone cells long after total body gamma irradiation. Hence, IL-1, or proteins regulated by this cytokine, appears to be the same stromal growth factor previously observed in the serum of irradiated animals. Our data demonstrate sev- eral non-canonical functions of IL-1. In addition, the presence of up-regulated levels of IL-1 long after irra- diation points to an unknown mechanism governing its gene expression. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Two different types of stem cells exist in the bone marrow of adult animals – hematopoietic stem cells and mesenchymal stem cells (MSC). After bone marrow plug is implanted under the renal capsule of syngeneic recipient, a hematopoietic ectopic focus forms. Stromal components develop de novo in this type of focus due to MSC from the implant, and hematopoietic cells migrate to the focus from the bone marrow of the recipient [1]. After this fo- cus is transferred into secondary recipients, a new focus is formed de novo by MSC from the implanted focus. The ability of MSC to serially transfer the hematopoietic stromal microenvironment demonstrated their capacity for self-renewal. It was demonstrated that the size of the foci formed in gamma- irradiated recipients increased 2–3-fold compared to that in non- irradiated recipients [1]. These enlarged hematopoietic ectopic foci form in irradiated recipients regardless of the amount of time that passes between irradiation and bone marrow plug implantation. However, retransplantation of enlarged foci from irradiated recipients to non-irradiated ones results in the formation of sec- ondary foci of normal size. These data suggest that stable numbers of MSC are present in the foci and that cells more mature than their MSC precursors are able to form an additional hematopoietic terri- tory upon corresponding induction but are unable to transfer this microenvironment into secondary recipients. The numbers of hematopoietic niches, mononuclear hematopoietic cells and prim- itive multipotent hematopoietic precursor cells – the spleen colony forming units – are significantly increased in the foci formed in irradiated recipients. Long-term repetitive injections of blood ser- um from irradiated mice into syngeneic non-irradiated bone mar- row plug recipients also lead to the formation of enlarged foci. Hence, the blood of irradiated animals must contain an activity that induces growth of a hematopoietic microenvironment [1]. The method used to examine the activity that stimulates growth of the stromal microenvironment was developed in culture [2] but it was unable to clarify the nature of this activity. In this study we demonstrated, that IL-1 beta is one of the components of this activity. IL-1 beta is one of the key members of the IL-1-like family of cytokines [3]. This family presently consists of 11 proteins that regulate inflammation caused by bacterial or viral infections or in 1043-4666/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cyto.2013.07.003 ⇑ Corresponding author. Tel.: +7 910 432 2870. E-mail addresses: bigchel@pochta.ru (A.E. Bigildeev), ksyna2@yandex.ru (O.A. Zhironkina), lubkova.ksu@yandex.ru (O.N. Lubkova), ndrize@yandex.ru (N.J. Drize). Cytokine xxx (2013) xxx–xxx Contents lists available at ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Please cite this article in press as: Bigildeev AE et al. Interleukin-1 beta is an irradiation-induced stromal growth factor. Cytokine (2013), http://dx.doi.org/ 10.1016/j.cyto.2013.07.003