Regulation of human peripheral blood monocyte collagenase by prostaglandins and anti-inflammatory drugs |
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| Institution: | 1. Department of Nutrigenomics and Bromatology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200 Sosnowiec, Poland;2. Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200 Sosnowiec, Poland;3. Institute of Electrical Drives and Machines KOMEL, 188 Rozdzienskiego Street, 40-203 Katowice, Poland;4. Department of Medical Genetics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200 Sosnowiec, Poland;1. School of Biotechnology, Southwest University, Chongqing 400716, China;2. School of Life Sciences, Southwest University, Chongqing 400716, China;1. São Paulo State University (UNESP), Department of Biology, Institute of Biosciences, Avenida 24-A, nº 1515, Bela Vista, CEP 13506-900, Rio Claro, São Paulo, Brazil;2. Heath Sciences Nucleus, Hermínio Ometto University Center, UNIARARAS, Avenida Dr. Maximiliano Barutto, nº 500, Jd. Universitário, Araras, São Paulo, CEP 13607-339, Brazil;3. Structural and Functional Biology Laboratory (LABEF), Federal University of São Carlos – UFSCAR, Rodovia João Leme dos Santos, Km 110 - SP-264, CEP 18052-780, Sorocaba, São Paulo, Brazil;4. Graduate Program in Biomedical Sciences, Hermínio Ometto University Center, UNIARARAS, Avenida Dr. Maximiliano Barutto, nº 500, Jd. Universitário, CEP 13607-339, Araras, São Paulo, Brazil;5. Reproductive Biology Laboratory, Structural and Functional Biology Department, State University of Campinas – UNICAMP, CP. 6109, Campinas, São Paulo, CEP 13083-863, Brazil |
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| Abstract: | Macrophages, which produce the collagenolytic enzyme collagenase, are commonly found at sites of connective tissue destruction in chronic inflammatory lesions. Since tissue macrophages are derived from circulating peripheral blood monocytes, we used these less-differentiated, more readily available cells to examine the production and regulation of collagenase. Human monocytes, isolated in large quantities by counterflow centrifugal elutriation, were shown to produce substantial amounts of collagenase when stimulated by concanavalin A (Con A) and to a lesser extent with lipopolysaccharide, while unstimulated monocyte cultures produced negligible collagenase. Collagenase was detected in the culture media within the first 24 hr of culture after activation with peak production at 48 hr. Analysis of the intracellular regulation of collagenase revealed that synthesis of this enzyme required a prostaglandin (PGE2)-dependent step since indomethacin-inhibited enzyme synthesis was reversed by PGE2. Additionally, dibutyryladenosine cyclic monophosphate (dBcAMP) restored collagenase synthesis in indomethacinblocked cultures, indicating a PGE2-dependent generation of cAMP requirement for collagenase production similar to that demonstrated in experimental animals systems. In additional studies, anti-inflammatory drugs which are known to modulate connective tissue destruction were analyzed for their influence on monocyte-derived collagenase. Dexamethasone, colchicine or retinoic acid all inhibited collagenase synthesis by monocytes in a dose-dependent manner although the effect of these drugs on monocyte PGE2 synthesis differed. Dexamethasone inhibited PGE2 synthesis, which resulted in the suppression of collagenase. However, PGE2 production was unaffected by colchicine whereas retinoic acid caused a significant increase in PGE2 levels. Inhibition of collagenase synthesis by dexamethasone, but not colchicine or retinoic acid, could be reversed by PGE2 or phospholipase A2. These findings provide insight into the intracellular events regulating monocyte collagenase synthesis and also implicate monocytes as a target of anti-inflammatory agents which ameliorate connective tissue degradation associated with chronic inflammatory lesions. |
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