Blood mononuclear cells from patients with
rheumatoid arthritis produce the lymphokine,
leukocyte inhibitory factor (LIF) in response to
collagens in vitro, and blood monocytes release
prostaglandins (
PGE2) and
a factor, mononuclear cell factor (MCF) which stimulates
collagenase and
PGE2 production by cultured synovial cells. We therefore examined the effect of
collagens on the production of
PGE2 and MCF. Blood mononuclear cells from 6 patients with
rheumatoid arthritis and 6 normal subjects were cultured in native human types I, II, or III
collagen-coated tubes, or with
streptokinase-
streptodornase (SK-SD), and the supernatant media derived from these cultures analyzed for the presence of MCF,
PGE2, and LIF. Types II and III
collagens, as well as SK-SD, markedly stimulated MCF production by the cells from all 12 subjects (MCF activity, expressed as a mean stimulation index (SI) +/- SEM, was 43 +/- 12 for type II, 33 +/- 7 for type III, and 37 +/- 23 for SK-SD).
Type I collagen was less stimulatory (mean SI 10 +/- 7). Cells from the patients with
rheumatoid arthritis, but not the normal subjects, produced LIF in response to types II or III
collagens but not to
type I collagen.
PGE2 production by blood mononuclear cells paralleled that of MCF, although abrogation of
PGE2 release with
indomethacin did not reduce MCF production. alpha chains purified from denatured
collagens also stimulated MCF production. Using cells from patients with
rheumatoid arthritis,
type II collagen stimulated production of all three factors in the presence of
polymyxin B or
fibronectin-depleted serum, suggesting, respectively, that neither
endotoxin nor
fibronectin were responsible for their generation. Monocytes, purified from normal blood by an adherence technique, but not lymphocytes depleted of monocytes, released MCF and
PGE2 when cultured with
type II collagen. These results demonstrate that
collagens can act as
ligands to stimulate monocytes, as well as
antigens to stimulate sensitized lymphocytes, to produce soluble factors that may contribute to the destruction of connective tissue.