Rhonna L. Cohen

Activation of p38 mitogen-activated protein kinase by norepinephrine in T-lineage cells.

The catecholamine norepinephrine (NE) stimulates T lymphocytes through a beta‐adrenergic receptor (βAR)/adenylyl cyclase (AC)/cyclic AMP (cAMP)/protein kinase A (PKA) pathway, leading to altered cell responsiveness and apoptosis. p38 Mitogen‐activated protein kinase (MAPK), a major intracellular signalling mediator for cellular and environmental stressors, is involved in the production of immune modulators and in the regulation of T‐cell development, survival and death. In these studies we investigated the relationship among NE signalling, p38 MAPK activity and T‐cell death. We showed that NE stimulation of BALB/c mouse thymocytes and S49 thymoma cells selectively increases the dual phosphorylation and activity of p38α MAPK. p38 MAPK activation involves the βAR, Gs protein, AC, cAMP and PKA, as determined through the use of a βAR antagonist, activators of AC and cAMP, and S49 clonal mutants deficient in Gs and PKA. Dual phosphorylation of p38 MAPK is also dependent on its own catalytic activity. Inhibition of p38 MAPK activity revealed its involvement in cAMP‐mediated activating transcription factor‐2 (ATF‐2) phosphorylation, Fas ligand messenger RNA (mRNA) up‐regulation, and cell death. These results identify a mechanism through which NE stimulation of the βAR/Gs/PKA pathway activates p38 MAPK, which can be potentiated by autophosphorylation, and leads to changes in T‐cell dynamics, in part through the regulation of Fas ligand mRNA expression.

Eicosanoids and Tumor Promotion

The concept of multistage carcinogenesis dates to observations by Peyton Rous and his colleagues in 1941, who noted a relationship between irritation and tumorigenesis in tar-induced tumors of rabbits (1). Since that time, a large volume of literature has emerged describing multi-stage carcinogenesis in skin and other organs. Some more recent reviews are listed in references 2–5.

The direct effects of biological response modifiers on epidermal cells

Biological response modifiers are agents which alter physiological processes and include growth factors, tumour promoters and pharmacological agents. This laboratory has been studying the mechanisms through which such agents alter epidermal homeostasis by using both in vivo systems and in vitro cell cultures.

Quantitative pathology of oral mucosal allografts in the rabbit

Abstract Quantitative analysis of four morphological components of the rejection reaction revealed differences between skin and mucosal allografts and between allografts and autografts of these tissues. Orthotopic skin or mucosal allografts were exchanged between pairs of rabbits matched or mismatched at the RLA locus of the major histocompatibility complex. Similar autografts were placed as controls. Quantitative microscopic examination of paraffin sections of all grafts, in which a standardized microscopic field was analysed, gave mean values for: (1) percentage of vessels with damaged walls; (2) fraction of vessel lumen occupied by blood cells or thrombus; (3) extravascular lymphocyte counts; (4) extravascular granulocytes counts. Significant differences were found between mismatched mucosal and mismatched skin allografts for all variables except lymphocyte counts. Mucosal and skin autografts differed significantly only in lymphocyte and granulocyte counts. Comparisons between mismatched allografts and autografts showed significant differences in all four variables in both mucosa and skin, whereas matched allografts and autografts of both tissues differed significantly for all variables except for the granulocyte count. Differences between autografts and allografts, whether RLA matched or mismatched, are clearly attributable to histocompatibility barriers in allografts. If the RLA locus had a significant effect on the 4 pathological components analysed, differences between matched and mismatched allografts would be evident. There being no such differences it is concluded that the minor histocompatibility loci play an important role in this type of immunological reaction. Differences in the reaction in oral mucosa and skin may be due to differences in the expression of histocompatibility antigens or tissue-specific antigens in these tissues and to factors of the local environment.