Am. J. Respir. Cell Mol. Biol., Vol 12, No. 6, Jun 1995, 669-675.
Calcitriol and its synthetic analogue MC 903 inhibit the interleukin-2- induced migration of human lymphocytes
LJ Fraher, AN Caveney and RG McFadden
Lung Biology Program, Lawson Research Institute of St. Joseph's Health Centre, London, Ontario, Canada.
Sarcoidosis is characterized by the accumulation of activated lymphocytes
in the lungs and other organs and by the spontaneous production of the
active form of vitamin D, calcitriol. We hypothesized that calcitriol may
modulate the responsiveness of human lymphocytes to the relevant biologic
mediator, interleukin-2 (IL-2). After culture for 48 h with
phytohemagglutinin, human peripheral blood lymphocytes migrated through
nitrocellulose filters, secured in microchemotaxis chambers, in response to
IL-2. When calcitriol at 1 nM was included in the cultures, the migratory
response to IL-2 was completely abrogated. This inhibitory effect was seen
despite the fact that cultured lymphocytes continued to express the IL-2
receptor and other activation markers. A similar but more rapid effect
could be demonstrated by including calcitriol in the lower well during our
3-h chemokinesis assay. Calcitriol blocked IL-2-induced lymphocyte
migration in a dose- dependent fashion. The synthetic noncalcemic vitamin D
analogue MC 903 was equally effective in this assay. IL-2-induced migration
could also be prevented by the protein kinase C inhibitor H-7, but
calcitriol appeared to be at least 1,000 times more potent. Our studies
suggest that calcitriol is a potent natural immunomodulator with rapid
suppressive effects that may be mediated through protein kinase C.
Synthetic analogues such as MC 903 may offer exciting therapeutic
opportunities.
