Protein kinase C mediates experimental colitis in the rat

Protein kinase C (PKC) plays an important role in the cell signal transduct ion of many physiological processes. In contrast to these physiological res ponses, increases in PKC activity have also been associated with inflammato ry disease states, including ulcerative colitis. The objective of this stud y was to examine the role of PKC as a causative mediator in initiation of e xperimentally induced colitis in the rat. Colitis was induced in rats by in trarectal (0.6 mi) instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS ; 75 mg/kg in 50% ethanol) or the PKC activator phorbol 12-myristate 13-ace tate (PMA; 1.5-3.0 mg/kg in 20% ethanol). Gross and histological mucosal da mage, mucosal neutrophil infiltration, mucosal PKC activity, and PKC protei n content for PKC isoforms alpha, beta, delta, and epsilon were assessed 2 h to 14 days after an inflammatory challenge. Both PKC activity and mucosal injury increased significantly within 4 h of TNBS treatment. PKC activity was maximal at 7 days and declined at 14 days, whereas mucosal damage becam e maximal at 1 day and declined after 7 days. In contrast, neutrophil infil tration as assessed by myeloperoxidase activity only increased 12 h after T NBS treatment, became maximal 1 day after TNBS administration, and declined thereafter. PKC beta, -delta, and -epsilon were increased in response to T NBS, whereas PKC alpha protein content was decreased. The PKC antagonists s taurosporine and GF-109203X (25 ng/kg iv) reduced TNBS-induced changes in m ucosal PKC activity and the degree of mucosal damage. In contrast, neutrope nia induced by antineutrophil serum treatment did not significantly affect the degree of injury or mucosal PKC activity. Furthermore, activation of mu cosal PKC activity with PMA also induced mucosal damage, which was also inh ibited by pretreatment with a PKC antagonist. In conclusion, these results suggest that increases in PKC activity play a causative role in TNBS-induce d colitis. The PKC-mediated response to TNBS does not appear to involve neu trophil infiltration.