High‐level production of alternatively spliced soluble interleukin‐6 receptor in serum of patients with adult T‐cell leukaemia/HTLV‐I‐associated myelopathy

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Abstract
We have previously shown, using human T‐cell lymphocytotrophic virus‐I (HTLV‐I)‐infected cell lines, that soluble interleukin‐6 receptor (sIL‐6R) is generated through an alternative splicing mechanism. In this study, we examined human sera for the presence of alternatively spliced soluble IL‐6R (AS‐sIL‐6R). We produced a monoclonal antibody (mAb) recognizing the unique sequence of AS‐sIL‐6R peptide, generated by an altered reading frame. We also made recombinant AS‐sIL‐6R protein in Spodoptera frugiperda‐9 (Sf‐9) cells carrying baculovirus, which encoded altered sIL‐6R or conventional IL‐6R cDNA. mAbs specifically recognized AS‐sIL‐6R, but not conventional IL‐6R, as demonstrated by Western blot analyses, fluorescence‐activated cell sorter, immunofluorescence analyses and enzyme‐linked immunosorbent assay (ELISA). We adapted an ELISA system and used it for detection of altered sIL‐6R in sera from 23 healthy persons, 12 patients with adult T‐cell leukaemia (ATL) and 13 patients with HTLV‐I‐associated myelopathy (HAM). Serum levels of AS‐sIL‐6R were 6·4 or 6·1 times greater in ATL (28·7±20·4 ng/ml, PP<0·0001) than in healthy individuals (4·5±2·1 ng/ml). High levels of AS‐sIL‐6R were also observed in plasma from rheumatoid arthritis patients and in persons with elevated levels of alanine aminotransferase (ALT), antinuclear antibody (ANA), or α‐fetoprotein (AFP). However, in human immunodeficiency virus‐1 (HIV‐1), hepatitis B virus (HBV) or hepatitis C virus (HCV)‐infected individuals, AS‐sIL‐6R levels were not elevated. In this study, we confirmed that AS‐sIL‐6R is indeed present in human sera. These observations suggest that alternative splicing of IL‐6R mRNA is of consequence in ATL, HAM and in some autoimmune diseases. The HTLV‐I‐infected T cells appeared to play an important role in AS‐sIL‐6R production.

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