Opioid peptides function as immunomodulatory molecules. Reports have linked the
opioid growth factor (OGF), [Met(5)]-
enkephalin, and its receptor OGFr to
autoimmune diseases. OGF repressed the incidence and magnitude of myelin oligodendrocyte-induced
experimental autoimmune encephalomyelitis in mice. Given the extensive connection between the immune system and
autoimmune diseases, the present study was conducted to examine the relationship of the OGF-OGFr axis and T lymphocyte proliferation. Splenic-derived mouse lymphocytes were stimulated with phytohemagglutin (PHA). All non-stimulated and PHA-stimulated T lymphocytes had immunoreactivity for OGF-like
enkephalin and OGFr. OGF markedly suppressed T lymphocyte number in a dose-dependent manner. However, PHA-stimulated T lymphocytes were not altered in cell number by a variety of natural and synthetic
opioid-related compounds, some specific for μ, δ, and κ
opioid receptors. Persistent blockade of
opioid receptors with the general
opioid antagonist naltrexone (NTX), as well as antibody neutralization of OGF-like
peptides, had no effect on cell number. Non-stimulated T lymphocytes exhibited no change in cell number when subjected to OGF or NTX. Treatment of T lymphocytes with siRNAs for μ, δ, or κ
opioid receptors did not affect cell number, and the addition of OGF to these
siRNA-exposed cultures depressed the population of cells. T lymphocytes treated with OGFr
siRNA also had a comparable number of cells to control cultures, but the addition of OGF did not alter cell number.
DNA synthesis in PHA-stimulated T lymphocytes exposed to OGF was markedly decreased from PHA-stimulated cultures receiving vehicle, but the number of cells undergoing apoptosis or
necrosis in these cultures was similar to control levels. T lymphocytes subjected to
siRNA for p16 and/or p21 had a comparable number of cells compared to controls, and treatment with OGF did not depress cell number in preparations transfected with both p16 and p21
siRNA. These data reveal that the OGF-OGFr axis is present in T lymphocytes and is capable of suppressing cell proliferation. However, T lymphocytes are not dependent on the regulation of cell proliferation by this system. The results showing that the OGF-OGFr axis is an
immunosuppressant, offers explanation for reports that
autoimmune diseases can be modulated by this system.