ACTIVATION OF PROTEIN-KINASE-C BY MYCOBACTERIAL CORD FACTOR, TREHALOSE 6-MONOMYCOLATE, RESULTING IN TUMOR-NECROSIS-FACTOR-ALPHA RELEASE IN MOUSE LUNG TISSUES

Cord factors are mycoloyl glycolipids in cell walls of bacteria belong ing to Actinomgcetales, such as Mycobacterium, Nocardia and Rhodococcu s. They induce granuloma formation in the lung and interstitial pneumo nitis, associated with production of macrophage-derived cytokines. We studied how cord factors induce biological activities in the cells. Co rd factors isolated from M. tuberculosis, trehalose 6-monomycolate (mT MM) and trehalose 6,6/-dimycolate (mTDM), enhanced protein kinase C (P KC) activation in the presence of phosphatidylserine (PtdSer), diacylg lycerol and Ca2+, and mTMM activated PKC alpha more strongly than PKC beta or gamma under the same assay conditions. Kinetic studies of mTMM in response to PKC activation revealed that mTMM increased the appare nt affinity of PKC to Ca2+ in the presence of both PtdSer and diolein. Although this is similar to observations with unsaturated fatty acids , such as arachidonic acid, mTMM was synergistic with PtdSer for PKC a ctivation, but arachidonic acid was not. mTMM was also different as re gards PKC activation, as phorbol ester was. A single i.p. administrati on of mTMM to mouse induced tumor necrosis factor-alpha (TNF-alpha) in serum and in the lung, which is a unique target tissue of cord factor s. Based on our recent finding that TNF-alpha is an endogenous tumor p romoter, the correlation between lung cancer and pulmonary tuberculosi s is discussed.