MECHANISMS OF CYTOKINE PRODUCTION BY FIBROBLASTS - IMPLICATIONS FOR NORMAL CONNECTIVE-TISSUE HOMEOSTASIS AND PATHOLOGICAL CONDITIONS

Fibroblasts actively participate in cellular immune responses in conne ctive tissues, when activated by signals abundant at inflammatory site s, ie. cytokines and bacterial products. This is manifested by the gen eration of proinflammatory cytokines and by presenting antigens to pro liferating T cells. The array of cytokines generated by immune-activat ed fibroblasts is determined by the stimulant and is controlled at mul tiple regulatory levels, such as transcription, translation, posttrans lational modifications, the signal transduction pathways which are act ivated, the timing of expression as well as compartmentation within th e producing cell. In general, cytokines with potential of tissue damag e, i.e. IL-1 alpha and, to a lesser extent, IL-6, are more tightly reg ulated than cytokines with restricted target cell specificity (i.e. CS Fs). Deviations in the pattern of expression of IL-1 alpha in patholog ical conditions affecting connective tissues are described; a long-las ting suppression of IL-1 alpha production was observed in dermal fibro blasts of mice suffering from chronic graft-vs.-host disease (cGVHD), while some oncogene-transformed fibroblastoid cell lines were shown to generate this cytokine in a constitutive manner and as a result expre ssed reduced tumorigenicity. The latter is due to the adjuvant effects of IL-1 alpha, expressed by the malignant cells, which induce potent antitumor specific immune responses which ultimately lead to its eradi cation. Understanding the molecular mechanisms which control cytokine production in fibroblasts may enrich our knowledge of connective tissu e homeostasis and deviations from it in pathological states. The latte r may also lead to the development of novel therapeutical means for co ntrolling chronic inflammatory diseases or malignancies.