CYTOKINE REGULATION OF PARATHYROID HORMONE-RELATED PROTEIN MESSENGER-RIBONUCLEIC-ACID LEVELS IN MOUSE SPLEEN - PARADOXICAL EFFECTS OF INTERFERON-GAMMA AND INTERLEUKIN-4

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 tha t, like cytokines, PTHrP is induced in the spleen during the response to sublethal doses of endotoxin [lipopolysaccharide (LPS)] an effect t hat is mediated by tumor necrosis factor (TNF). As complex cytokine ca scades 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 mu g), a cy tokine that usually synergizes with TNF, inhibited LPS induction of Ou J (OuJ) and LPS-resistant C3H/HeJ (HeJ) mice. The stimulation of splen ic PTHrP mRNA levels caused by the administration of TNF alpha or inte rleukin-lp was similarly inhibited by IFN gamma, a type II interferon. In contrast, IFN alpha (50 mu g), a type I interferon, stimulated spl enic levels of PTHrP mRNA. IL-4, a prototypical antiinflammatory cytok ine, also had a paradoxical effect on LPS induction of splenic PTHrP m RNA levels. Instead of inhibiting LPS induction of splenic PTHrP mRNA levels in OuJ or HeJ mice, IL-4 (200 ng) actually stimulated PTHrP mRN A levels. These complex cytokine interactions suggest that the express ion of PTHrP in response to infectious or inflammatory stimuli depends on the counterbalancing effects of the specific cytokine networks ind uced by each stimulus.