Influence of urokinase gene knockout on levels of TNF- α and its receptors in the brain of mice with experimental melanoma developing in presence of chronic neurogenic pain

Background. Despite the functional multiplicity and complexity of TNF- α effects, its role in the central nervous system in the development of various pathological conditions of the body is still poorly understood.

Objective. Analyzing the dynamics of TNF- α and its receptors in the brain of urokinase (uPA-) gene-knockout mice with malignant growth in presence of chronic neurogenic pain (CNP).

Design and methods. The study included male and female mice of two strains: C57BL/6 (n = 80) and C57BL/6-PlautmI.IBug-ThisPlau6FDhu/ GFDhu (n = 56). A CNP model was created in animals of the main groups by the bilateral sciatic nerve ligation; 2 weeks after it, B16/F10 melanoma was transplanted under the skin of the back. The comparison group — sham operated animals with transplanted melanoma. Control groups — sham operated animals and animals with CNP. On day 21 of the melanoma growth, the mice were decapitated, and levels of TNF- α, sTNF- α R1 and sTNF- α R2 were determined in the cerebral tissues by ELISA.

Results. High levels of TNF- α (by 5.6 times) and low TNF- α R1 (by 2.1 times) were registered in the brain of uPA- males, while no changes were registered in females. Under the influence of CNP, brain levels of TNF- α became similar in male and female mice; TNF- α levels in uPA- mice were twice higher than in animals with the normal genome. The CNP stimulating effect on the malignant process in uPA- mice was based: in females — on an increase in the cerebral concentration of TNF- α R2 (by 1.7 times, p<0.05), in males — on TNF- α reduction (by 2.2 times).

Conclusion. The specificity of the fibrinolytic status of mice determines the course of subcutaneously transplanted melanoma in presence of pain, and one of the mechanisms of this phenomenon involves a change in the functioning of the brain TNF- α system, depending on the animal gender.

1. Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol. 2010; 125(2 Suppl 2): S53-72.

2. Probert L. TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience. 2015; 302: 2-22.

3. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, et al. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014; 15(2): 135-147.

4. Fischer R, Kontermann RE, Maier O. Targeting sTNF/TNFR1 signaling as a new therapeutic strategy. Antibodies. 2015; 4: 48-70.

5. Steeland S, Puimege L, Vandenbroocke RE, et al. Generation and characterization of small single domain antibodies inhibiting human tumor necrosis factor receptor 1. J Biol Chem. 2015; 290(7): 4022-4037.

6. Kit OI, Frantsiyants EM, Kotieva IM, et al. Dynamics of the tissue system of plasminogen regulators in cutaneous melanoma with chronic pain in female mice. Translyatsionnaya meditsina=Translational Medicine. 2018; 5(2): 38-46. In Russian

7. Frantsiyants EM, Kaplieva IV, Surikova EI et al. Effect of urokinase gene-knockout on growth of melanoma in experiment. Sibirskiy Nauchny Meditsinskiy Zhurnal=Siberian Scientific Medical Journal. 2019; 39(4): 62-70. In Russian

8. Idell RD, Florova G, Komissarov AA, et al. The fibrinolytic system: A new target for treatment of depression with psychedelics. Med Hypotheses. 2017; 100: 46П53.

9. Liguz-Lecznar M, Zakrzewska R, Kossut M. Inhibition of Tnf-α R1 signaling can rescue functional cortical plasticity impaired in early post-stroke period. Neurobiol Aging. 2015; 36(10): 2877-2884.

10. Chen BL, Li YQ, Xie DH, et al. Blocking TNF-α with infliximab alleviates ovariectomy induced mechanical and thermal hyperalgesia in rats. Neurol Sci. 2012; 33(3): 527-533.

11. Bouris P, Skandalis SS, Piperigkou Z, et al. Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biol. 2015; 43: 42-60.

12. Liu Y, Zhou L-J, Wang J, et al. TNF-a differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J Neurosci. 2017; 37(4): 871-881.

13. Buoncervello M, Maccari S, Ascione B, et al. Inflammatory cytokines associated with cancer growth induce mitochondria and cytoskeleton alterations in cardiomyocytes. J Cell Physiol. 2019; 234(11): 2045320468.

14. Camara ML, Corrigan F, Jaehne EJ, et al. TNF-α and its receptors modulate complex behaviours and neurotrophins in transgenic mice. Psychoneuroendocrinology. 2013; 38(12): 3102-3114.