K(+) channel-blocking alkoxypsoralens inhibit the immune response of encephalitogenic T line cells and lymphocytes from Lewis rats challenged for experimental autoimmune encephalomyelitis.
Alkoxypsoralens, known as DNA photomodifying agents, have been shown to block voltage-dependent K(+) channels (Kv) as well as to alleviate functional deficits in certain multiple sclerosis (MS) patients in a manner similar to 4-aminopyridine. Since Kv channel blockers are known to inhibit T cell-mediated immune responses both in vitro and in vivo, we investigated the effects of three alkoxypsoralens, 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP), and 5,8-diethoxypsoralen (H37), on the following parameters: (1) whole-cell K(+) currents of encephalitogenic, myelin basic protein-specific memory T cell line cells (MBP-TCLC) derived from Lewis rats as measured by patch-clamp technique, (2) proliferation of MBP-TCLC and lymph node cells (LNC) from Lewis rats challenged for experimental autoimmune encephalomyelitis (EAE) by immunisation with spinal cord homogenate as measured by 3H-thymidine incorporation, (3) interferon-gamma (IFN-gamma) secretion of MBP-TCLC as measured by ELISA, and (4) IFN-gamma gene expression of LNC as measured by quantitative reverse transcription polymerase chain reaction (RT-PCR) with ELISA-detection. The examined alkoxypsoralens exhibited suppressive effects on the measured parameters with the same sequence of efficacy: H37>5-MOP>8-MOP. We, therefore, conclude that Kv channel-blocking alkoxypsoralens interfere with voltage-controlled signal transduction in lymphocytes and might thereby suppress immune responses in autoimmune diseases of the central nervous system and most likely also in other autoimmune disorders. Thus, alkoxypsoralens, especially the non-phototoxic substance H37, are new candidates for further studies on K(+) channel blocking immunosuppressive drugs. The agents may exert a dual beneficial effect on demyelinating diseases like MS, because they could attenuate the inflammatory process and improve axonal conductivity.
Strauss
U
U
Department of Neurology, University of Rostock, P.O. Box 100888, Gehlsheimer Str. 20, D-18147, Rostock, Germany.
Wissel
K
K
Jung
S
S
Wulff
H
H
Hänsel
W
W
Zhu
J
J
Rolfs
A
A
Mix
E
E
D015761:4-Aminopyridine / Q000494:pharmacology; D000078223:5-Methoxypsoralen; D000818:Animals; D002460:Cell Line; D003208:Concanavalin A; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D011564:Furocoumarins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008730:Methoxsalen / Q000031:analogs & derivatives* / Q000494:pharmacology; D004676:Myelin Basic Protein; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
C115584:5,8-diethoxypsoralen; D011564:Furocoumarins; D004676:Myelin Basic Protein; D026902:Potassium Channel Blockers; D003208:Concanavalin A; D000078223:5-Methoxypsoralen; D007371:Interferon-gamma; D015761:4-Aminopyridine; D008730:Methoxsalen