Cell behavior and signal molecule involvement in a case study of malignant histiocytosis: a negative model of morphine as an immunoregulator.
In a patient diagnosed with histiocytic medullary reticulosis (HM), we examined immunocytes for their responsiveness towards known signaling molecules. Both the granulocytes and monocytes were found to exhibit a high level of spontaneous activation (96% compared to normal cells 7%; P < 0.001). These cells could not be downregulated when exposed to morphine. Following patient treatment with doxorubicin and cyclophosphamide, the immunocytes still exhibited a high spontaneous activation. They responded to morphine exposure in vitro with a cell rounding and becoming immobile for only 20 min whereas normal cells would remain round and immobile for up to 1-2 h. An examination of the plasma from the HM patient revealed that monocyte colony stimulating factor (MCSF) levels were elevated (6.4 and 5.78 compared to a control range of 1-1.75 ng/ml). In the HM patient, the immunocytes did not express the opiate selective and opioid peptide insensitive receptor, mu3, supporting the lack of opiate action. Given this finding, we incubated normal monocytes with MCSF and found that it significantly reduced the mu3 Bmax. Given the role of intracellular calcium in the activation process of immunocytes, we examined the action of various calcium channel blockers for their ability to inhibit the activated HM monocytes. The agents (nimodipine, cardiazem, and verapamil; 10[-9] M) were able to inhibit the HM-associated chemokinesis. Taken together, the data indicate that in the HM patient the immunocytes appear to be overactivated because stimulatory molecules are high and have the ability to downregulate the normal "braking" process. Additionally, the data indicate that MCSF deregulation may be involved as an initiating factor for this disorder.
Fricchione
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Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. GLFricchio@BWH.harvard.edu
Cytryn
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Bilfinger
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Stefano
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D000368:Aged; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D003520:Cyclophosphamide / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D004317:Doxorubicin / Q000627:therapeutic use; D017809:Fatal Outcome; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D054747:Histiocytic Sarcoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D009020:Morphine / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
D000701:Analgesics, Opioid; D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D002121:Calcium Channel Blockers; D016207:Cytokines; D017450:Receptors, Opioid, mu; D009020:Morphine; D004317:Doxorubicin; D016173:Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide