Endorphin and enkephalin ameliorate excessive synovial cell functions in patients with rheumatoid arthritis.
OBJECTIVE
To determine whether endorphin (END) and enkephalin (ENK) modulate excessive synovial cell functions in patients with rheumatoid arthritis (RA).


METHODS
Effects of leucine-enkephalin (leu-ENK), methionine-enkephalin (met-ENK), and beta-endorphin (END) on proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells were analyzed by immunoblotting, and their mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR) using limiting dilution of complementary DNA. Expression of opioid receptors on RA synovial cells was assessed by immunohistochemical staining, radioreceptor assay, and RT-PCR.


RESULTS
Leu-ENK, met-ENK, and END inhibited tumor necrosis factor-alpha and interleukin 1beta production at the level of mRNA expression. ENK and END inhibited MMP-9 production and its enzymatic activity by RA synovial cells. The mu-subtype opioid receptor was expressed in the RA synovial lining and sublining cells. Radioreceptor assay suggested expression of high affinity receptor for END on RA synovial cells. The mu-subtype opioid receptor-specific antagonist, naloxone, reversed the inhibitory effect of the opioid peptides. The opioid peptides inhibited nuclear translocation and phosphorylation of the transcription factor, cyclic AMP responsive element binding protein (CREB) in RA synovial cells.


CONCLUSIONS
Leu-ENK, met-ENK, and END inhibited excessive RA synovial cell functions in vitro. The opioid hormones may have not only antinociceptive action, but also antiinflammatory effects on synovitis itself in RA.
Takeba
Y
Y
Department of Immunology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Suzuki
N
N
Kaneko
A
A
Asai
T
T
Sakane
T
T
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008875:Middle Aged; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000235:genetics; D018847:Opioid Peptides / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology* / Q000276:immunology; D013585:Synovitis / Q000188:drug therapy / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D001615:beta-Endorphin / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D007375:Interleukin-1; D018847:Opioid Peptides; D011957:Receptors, Opioid; D014409:Tumor Necrosis Factor-alpha; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D001615:beta-Endorphin; D020780:Matrix Metalloproteinase 9