Induction of the synthesis of the C-X-C chemokine interferon-gamma-inducible protein-10 in experimental canine endotoxemia

Endotoxemia is associated with a systemic inflammatory response leading to organ-specific leukocyte recruitment and tissue injury. Chemokine expressio n has been demonstrated in various models of sepsis and may mediate tissue infiltration with inflammatory cells. In this study we examined expression of the C-X-C chemokine interferon-gamma -inducible protein-10 (IP-10), a po tent T-lymphocyte chemoattractant, in a canine model of endotoxemia and inv estigated mechanisms of cytokine-mediated IP-10 induction in endothelial ce lls. Control canine tissues showed negligible expression of IP-10 message, with the exception of the spleen. Endotoxemic dogs demonstrated a robust in duction of IP-10 mRNA in the heart, lung, kidney, liver, and spleen. Immuno histochemical studies indicated that IP-10 was predominantly localized in c ardiac venular endothelial cells, bronchial epithelial cells, renal mesangi al cells, and in the splenic red pulp of endotoxemic dogs. In addition, IP- 10 expression was associated with T-lymphocyte infiltration in canine tissu es. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 be ta) induced a marked upregulation of IP-10 message in canine venular endoth elial cells. IP-10 expression in TNF-alpha -stimulated endothelial cells pe aked at 6 h of stimulation and returned to baseline levels after 24 h. In a ddition, macrophage colony-stimulating factor (M-CSF) induced a dose-depend ent induction of IP-10 mRNA in canine endothelial cells. M-CSF-mediated IP- 10 expression peaked after 6 h of incubation and returned to baseline level s after 24 h. Canine endotoxemia is associated with a robust early expressi on of IP-10 in multiple tissues. IP-10 induction may be important in regula ting lymphocyte recruitment and function. TNF-alpha, IL-1 beta, and M-CSF a re potent inducers of IP-10 in canine endothelial cells and may indirectly mediate lymphocyte chemotaxis and activation in inflammatory processes.