Mechanisms of cytokine production by fibroblasts-implications for normal connective tissue homeostasis and pathological conditions.

Fibroblasts actively participate in cellular immune responses in connective tissues, when activated by signals abundant at inflammatory sites, i.e. cytokines and bacterial products. This is manifested by the generation of proinflammatory cytokines and by presenting antigens to proliferating T cells. The array of cytokines generated by immune-activated fibroblasts is determined by the stimulant and is controlled at multiple regulatory levels, such as transcription, translation, posttranslational modifications, the signal transduction pathways which are activated, the timing of expression as well as compartmentation within the producing cell. In general, cytokines with potential of tissue damage, i.e. IL-1 alpha and, to a lesser extent, IL-6, are more tightly regulated than cytokines with restricted target cell specificity (i.e. CSFs). Deviations in the pattern of expression of IL-1 alpha in pathological conditions affecting connective tissues are described; a long-lasting suppression of IL-1 alpha production was observed in dermal fibroblasts 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 expressed 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 eradication. Understanding the molecular mechanisms which control cytokine production in fibroblasts may enrich our knowledge of connective tissue homeostasis and deviations from it in pathological states. The latter may also lead to the development of novel therapeutical means for controlling chronic inflammatory diseases or malignancies.