Cytokine regulation of parathyroid hormone-related protein messenger ribonucleic acid levels in mouse spleen: paradoxical effects of interferon-gamma and interleukin-4

Abstract

Under normal physiological conditions, PTH-related protein (PTHrP) is produced in a wide variety of tissues and is thought to act locally in an autocrine or paracrine fashion more analogous to cytokines than to classic hormones such as PTH. In addition, we have recently shown that, like cytokines, PTHrP is induced in the spleen during the response to sublethal doses of endotoxin [lipopolysaccharide (LPS)] an effect that is mediated by tumor necrosis factor (TNF). As complex cytokine cascades are induced in response to infectious or inflammatory stimuli, the effects of other prototypical inflammatory [interferon-gamma (IFN gamma)] or antiinflammatory [interleukin-4 (IL-4)] cytokines on PTHrP gene expression were studied. Paradoxically, IFN gamma (50 micrograms), a cytokine that usually synergizes with TNF, inhibited LPS induction of splenic PTHrP messenger RNA (mRNA) levels in LPS-sensitive C3H/OuJ (OuJ) and LPS-resistant C3H/HeJ (HeJ) mice. The stimulation of splenic PTHrP mRNA levels caused by the administration of TNF alpha or interleukin-1 beta was similarly inhibited by IFN gamma, a type II interferon. In contrast, IFN alpha (50 micrograms), a type I interferon, stimulated splenic levels of PTHrP mRNA. IL-4, a prototypical antiinflammatory cytokine, also had a paradoxical effect on LPS induction of splenic PTHrP mRNA levels. Instead of inhibiting LPS induction of splenic PTHrP mRNA levels in OuJ or HeJ mice, IL-4 (200 ng) actually stimulated PTHrP mRNA levels. These complex cytokine interactions suggest that the expression of PTHrP in response to infectious or inflammatory stimuli depends on the counterbalancing effects of the specific cytokine networks induced by each stimulus.

Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen

“…Another role of PTHrP, as a proinflammatory cytokine, has also been reported. TNF-␣ and IL-1␤ stimulate PTHrP expression in splenic stromal cells, 22,23 while PTHrP induces IL-6 and LIF expression in osteo- PTHrP antibody (100 g IgG/mouse, solid circles) and/or PBS (control, open circles) were administered into the peritoneal cavity for 6 days. Body weight and tumor volume were measured daily, and blood ionized calcium was measured on days 0, 2, 4 and 6 (death).…”

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

“…The widespread expression of PTHrP in normal tissue was the first evidence that the hormone had a role in normal physiology. In addition to the PTH-like effects, emerging work testifies to the fact that PTHrP plays a role in (1) the regulation of cartilage differentiation and bone formation (Minina et al 2001), (2) the growth and differentiation of skin (Wysolmerski et al 1994b), mammary gland (Wysolmerski et al 1998) and teeth (Philbrick et al 1998), (3) cardiovascular function (Schluter & Piper 1998), (4) transepithelial calcium transport in mammary epithelia and placenta (Wysolmerski et al 1994a, Kovacs et al 1996, (5) relaxation of smooth muscle in uterus, bladder, arteries and ileum (Thiede et al 1990, Yamamoto et al 1992, Botella et al 1994, Pirola et al 1994) and (6) host immune function (Funk et al 1994(Funk et al , 1995. Normal subjects do not have detectable circulating levels of PTHrP, suggesting that in normal physiology PTHrP acts as a local regulator or cytokine in the tissues where it is produced.…”

The Increase of Parathyroid Hormone-Related Peptide and Cytokine Levels in Synovial Fluid of Elderly Rheumatoid Arthritis and Osteoarthritis.

“…Moreover regulation of PTHrP mRNA by cytokines was demonstrated in mouse spleen indicating the counterbalancing effects by either infection or inflammation [7]. Therefore it is possible to assume that PTHrP secreted by articular cartilage or synovial cells play a role in the inflammatory process of RA.…”