In the natural state, cytokine receptor (CK-R) mainly contains membrane-bound cytokine receptor (mCK-R) and soluble cytokine receptors in body fluids such as serum. Soluble cytokine receptor, sCK-R) exists in two forms. The complex biological activity of cytokines is mainly mediated by the binding of the base to the corresponding mCK-R, while sCK-R has a unique biological significance. In recent years, the relationship between sCK-R levels and certain diseases has received increasing attention from scholars. Partially recombinant sCK-R (rsCK-R) genetic engineering products have entered clinical validation, and basic research on the mechanism, structural characteristics and basic immunological functions of sCK-R has also made great progress.
(1) The mechanism and function of sCK-R
Human T cell leukemia virus type I (HTLV-I) infected cells such as HUT102B2 and MT-2, myeloid leukemia cells (HL-60, KG1) and some human B cell lines (Raji) express a variety of mCK-R In addition, sCK-R can be produced in different ways, such as HUT102B2 cell culture. High levels of sCK-2R and sIL-6R can also be detected in Fengqing. Human PMC also produced a large amount of sCK-2R and sCK-6R after being stimulated by PHA in vitro.
1. Generation of sCK-R Most of sCK-R is mainly derived from the detachment of membrane receptors, so dissolving membrane receptor yang cells is a method for obtaining a large amount of sCK-R. Most of the sCK-R amino acid sequences are homologous to the extracellular domain of mCK-R, lacking only the transmembrane and cytoplasmic regions, but can still specifically bind to the corresponding ligands. In addition to the cleavage and shedding of membrane receptors to produce the sCK-R form, another mechanism for producing sCK-R is through the different splicing of the receptor mRNA to produce secreted mRNA, which is secreted directly into the cell by translation. It has been confirmed that the cell The same type of cDNA can be contained in the same CK-R. The sIL-4R, sIL-5Rα chain, sIL-6Rα chain, sIL-7R, and sG-CSFR can be produced in this form.
sCK-R
Molecular weight (kDa)
(Soluble/membrane-bound) Receptor extracellular structure sCK-R production mechanism sCK-1R 47/68 (type II receptor) IGSF membrane receptor is liberated by protease hydrolysis and sheds sCK-2R 45/55 (α chain (Unclassified) Membrane receptor shedding sCK-4R /140 ERS Secreted mRNA translation, secretion sCK-5R /60 (α chain) ERS Membrane receptor detachment and secreted mRNA translation, secretion sCK-6R 50/80 (α Chain) IGSF+ERS Membrane receptor detachment and secretory mRNA translation, secretion sCK-7R /65 ERS Secreted mRNA translation, secretion sG-CSFR / IGSF+ERS Secreted mRNA translation, secretion sGM-CSFR /85 ERS membrane receptor Exfoliated sIFN-γR /90 interferon receptor family membrane receptor shedding sTNF-R 33/55 or 75 NGFR membrane receptor shedding.
2. Biological effects of sCK-R Most sCK-R binds to the corresponding cytokines with lower affinity than mCK-R, which may be related to sCK-R being single-stranded or lacking some structural regions. There are also sCK-Rs such as sIL-4R that bind to the corresponding ligands of native mIL-4R with the same affinity, even low doses of sIL-4R can specifically inhibit IL-4 induced cell proliferative responses. sCK-R exerts its unique immunological function in many ways.
(1) As a cytokine transporter, the cytokine is transported to the body for production, resulting in a high concentration of local cytokines to fully exert the biological effects of cytokines.
(2) It is a normal metabolic pathway of membrane receptors, which is beneficial for the cells in the activated state to return to normal levels.
(3) Competingly bind to the corresponding ligand of mCK-R to inhibit the biological effects mediated by mCK-R.
sCK-R and clinical
1. Detection of sCK-R levels in clinical applications. Detection of certain sCK-R levels to assist in the early diagnosis of certain diseases, to understand the development and outcome of the disease, and to assess the immune status and prognosis of patients, Clinical treatment also has certain guiding significance.
(1) Detection of sIL-2R: In recent years, domestic and foreign scholars have carried out a lot of research on sIL-2R, and found that its changes in serum and other unidentified levels are related to various clinical diseases such as organ transplant rejection and virality. The condition and course of infection, malignancy, trauma and autoimmune diseases are closely related (Table 4-21).
(2) Detection of other sCK-R: Recently, a 50kDa sIL-6R molecule called IL-6R-SUP was found in the urine, which promoted the growth of mouse plasmacytoma T1165 induced by low dose of IL-6. Plasma levels of sIL-6R were significantly elevated in patients with multiple myeloma. The serum sTNFR level was abnormally increased in patients with rheumatic diseases. High levels of sTNF-R were also detected in the spur of the cavity, and the active phase was significantly higher than the inactive phase. Only TNF-RII type sTNFR can be detected in women's urine, while urinary TNF-r I and TNF-RII sTNFR can be detected in pregnant women. The sTNFR level increases with gestational age, after delivery. This is followed by a protective mechanism that protects the fetus from TNF. High levels of sTNFR can also be detected in liver infective ascites and cancerous ascites. It has also been found that the increase in sTNFR levels is closely related to the decline in renal function in patients.
2. sCK-R in clinical application prospects Most sCK-R binds to cytokines and binds cytokines to membrane receptors, thereby inhibiting the biological activity of cytokines, and using sCK-R to reduce or prevent inflammatory cytokines The pathological damage provides a new therapeutic approach. Animal experiments showed that local injection of sIL-1R inhibited IL-1 mediated inflammatory response. sIL-1R can reduce the rejection of mouse allogeneic heart transplantation as well as experimental arthritis and allergic encephalitis in rats. In vitro sIL-1R can significantly inhibit the proliferation of bone marrow cells in patients with acute myeloid leukemia. Recently, the application of IL-1R genetic engineering products has begun clinical trials for the treatment of arthritis, diabetes, and prevention of organ transplant rejection. In vivo injection of sIL-4R in animals can prolong the survival of allogeneic grafts, inhibit GVHR, and reduce type I hypersensitivity. The use of sTNFR reduces the pathological damage mediated by TNF in autoimmune diseases and reduces septic shock.
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