Prostaglandins in inflammation and disease

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pholipase A 2 which is responsible for making arachidonic acid available for prostaglandin synthesis at the cell membrane. Thus, intracellular calcium levels are very important to both the formation and activities of the prostaglandins. ~T] J O H N L. NINNEMANN

Department of Surgery, University of California, San Diego, CA92093, USA.

References 1 Goodwin,J. S. and Webb, D. R. (1980) Clin. Immunol. lmmunopathol. 15, 106-122 2 Oates, J. A., Roberts, L. J., Sweetman, B. J., Maas, R. L., Gerkens, J. F. and Taber, D. F. (1980) in: Advancesin Prostaglandinand Thromboxane

Research(Samuelsson, B., Ramwell, P. W. and Paoletti, R., eds), Vol. 6, pp. 35-41, Raven Press, New York 3 Winkelstein, R. and Kelley, V. E. (1980) Clin. hnmunol. Immunopathol. 17, 212-218 4 Goodwin, J. S., Wiik, A., Lewis, M., Bankhurst, A. D. and Williams, R. C., Jr. (1979) Cell. Immunol. 43, 150-159 5 Parker, C. W. (1979)Ann. NYAcad. Sci. 332, 255 261 6 Stenson, W. F. and Parker, C. W. (1982) in: Prostaglandins(Lee, J. B., ed.), pp. 39-89, Elsevier, New York 7 Hadden, J. W., Coffey, R. G., Anathakrishnan, R. and Hadden, E. M. (1979)Ann. NYAcad. Sci. 332, 241-254 8 Hadden, J. W., Coffey, R. G. and Spreafico, F. (1977)Immunopharmacol0g;v, Plenum Publishing Corp., New York

9 Weissmann, G.(1980) CurrentConcepts:ProstaglandinsinAcutelnflammation, pp. 1-14, Upjohn Co., Kalamazoo 10 Zeigler, J. L. (1980) Current Concepts: Cancer and the Prostaglandins, pp. 15-22, Upjohn Co., Kalamazoo

Prostaglandins in inflammation and disease John L. Ninnemann Prostaglandins (PGs) were first linked with inflammation in studies showing that the mechanical irritation of rabbit eyes released a mediator, labeled 'irin', into the anterior chamber of the eye. Irin was later identified as a mixture o f P G E 2 and PGF2o (Ref 1). It is now recognized that any process leading to membrane disruption also leads to the release of PG. Carrageenan produces an acute inflammation when injected into the footpad of the rat and this model has been used extensively in the study of inflammation. Experiments using carrageenan have been credited with the discovery of indometacin (a cyclo-oxygenase inhibitor) and the identification of histamine, 5-hyclroxytryptamine (5-HT), the kinins, and the PGs as active elements in inflammation. Evidence has accumulated that the various oxidation products ofarachadonic acid are involved in producing all of the cardinal signs of inflammation. Vasodilatation (and thus redness) is caused by the release into the tissues of prostacyclin (PGIz), PGEI, PGE2, PGD2, and thromboxane (Tx)A~. The effects of these compounds are antagonized to a certain degree by the vasoconstrictive activity of the endoperoxides and PGF2~ (Ref 2). While only weakly active in producing swelling, PGG2, PGH2, PGI2, PGE and PGF contribute synergistically to edema formation by bradykinin and histamine 3. The role of PG in the induction of fever is at present unclear. Whereas arachadonic acid itself is pyrogenic, the known PG derivatives are by themselves not capable of causing fever. However, the non-steroidal anti-inflammatory agents such as indometacin drugs which interfere with PG synthesis, are antipyretic. It is thought, therefore, that some unknown derivatives of arachadonic acid are mediators of fever 3. Pain is also produced in inflammatory models by arachadonic acid, and by PGE 1 and PGE 2 in synergistic way with bradykinin and histamin&. The fifth cardinal sign of inflammation is loss of function and PG-mediated inhibition of cellular activity during inflammatory and immune responses is very clear. While PGs along with other mediators help to 'drive' Department of Surgery, University of California, San Diego, LaJolla, CA 92093, USA.

inflammatory reactions of all types, they are more important in some types of inflammation than in others. Their major role in the sunburn reaction, for example, is irrefutable. The early stages of sunburn can be completely reversed by the topical application of the cyclo-oxygenase inhibitor, indometacin +. It appears that the later stages of the sunburn response are promoted by mediators released by infiltrating leukocytes and PG seem to function in this inflammatory process by affecting the metabolism of these cells as well. The presence of PGE2, for example, is particularly related to the release of histamine 4. As a general rule, prostaglandins of the E series potentiate the actions of proinflammatory mediators, while prostaglandins of the F series counteract these effects 4. The leukotrienes, arachadonic acid derivatives produced as a result of lipoxygenase activity, are undoubtedly also major participants in inflammation but discussion of these compounds is beyond the scope of this review.

PGs and granulocyte function The concentration of PG is increased greatly in inflamed tissues and the degree of granulocyte infiltration into these tissues correlates directly with this concentration. More specifically local injection ofvasodilatory prostaglandins (PGE1 or PGE2) enhances the rate and degree of polymorphonuclear leukocyte (PMN) infiltration in response to a number of chemotactic stimuli 9. The chemotactic properties of PG, however, are not clear. One study has shown that PGEI (but not PGE 2 or PGF2~) has strong chemotactic activity 6, while another has shown chemotactic activity only for PGE 2 and only in the presence of albumin 7. Arachidonic acid metabolites have a clear effect upon P M N degranulation. Low concentrations induce degranulation of rabbit PMN, while PG derivatives of arachadonic acid generally block, for example, zymosaninduced degranulation and inhibit PMN aggregation 7, P M N are able to transform one PG to another by a mechanism dependent upon H202, the lysosomal enzyme myeloperoxidase and chloride ions, thus introducing the concept that P M N may themselves modulate the inflamo matory process 8 © 1984,ElsevierSciencePublishersB.V,Amsterdam 0167 4919/84/$02.00

174 P G p r o d u c t i o n b y the m o n o c y t e l m a c r o p h a g e Arachidonic acid metabolism plays an important role in macrophage-lymphocyte interactions, and in the role of the macrophage as a phagocyte. Macrophages are both active producers of PG and prominent participants in the cellular immune response. These cells are therefore likely to be a major source of the P G produced during inflammation, with other mononuclear cells contributing to a lesser extent 9. The experiments designed to determine such functions, however, are difficult to interpret since most employ impure cell populations. Moreover, cell function in these assays affected by the harvesting procedure employed. It is clear, however, that the monocyte/macrophage can produce the cyclo-oxygenase products PGI2, PGE2, PGF2~, and TxB 2 and that alveolar macrophages are particularly adept 7. PG synthesis by the macrophage can be induced by a number of stimuli including zymosan, Corynebacterium parvum, colchicine, antigen-antibody complexes, endotoxin, the calcium ionophore A23187, and concanavalin A1°. Gemsa et al. H have studied the inter-relationship between phagocytosis, PGE1 production and the production of cAMP in rat peritoneal macrophages. A greater, more prolonged cAMP response could be induced in macrophages phagocytozing zymosan by the presence of exogenous PGE 1. This process induced the release of endogenous PGE. Thus, macrophages exhibited an enhanced PG sensitivity with a concomitant increase in PG release. The alterations in both sensitivity and secretion of these mediators represent important components in a sensitive feedback loop controlling the macrophage response. In addition, there appears to be an inverse correlation between interleukin 1 ( I L l ) secretion and PGE production by sensitized cells lz. PGE 2 derived from macrophages inhibits the in-vitro clonal proliferation of committed" granulocyte-macrophage stem cells in bone marrow and controls the expression of Ia-like H L A - D R antigen on their surface 13. PG are apparently produced by macrophages in response to lectin stimulation of lymphocytes and in mixed lymphocyte cultures. These findings have been interpreted as indicating that macrophage release of P G can be lymphokine-induced ~4, This postulate suggests another possible mechanism for control of the immune response, that is, feedback control of macrophage activities by the lymphocyte. Macrophages contained in mixed lymphocyte cultures produce strikingly increased amounts of P G in cultures containing cells from a sensitized allograft recipient and the respective donor 15. Paradoxically, Anderson found that administration of exogenous PGE prolonged allograft survival in micC 6. Such studies illustrate the unresolved complexity of cellular interactions involving PGs.

Prostaglandin alteration of i m m u n e responsiveness in disease Malignancy T u m o r cells are one of the stimuli for the production of large amounts of PGE by the monocyte/macrophage and

Immunology Today, vol. 5, No. 6, 1984 PGs also inhibit the production of lymphokines which augment immune responsiveness and cytolysis. PG production may thus be one mechanism responsible for the 'escape' of tumor cells from immune surveillance 17. Indeed, it can be demonstrated that a diminished cellular immune response, in certain experimental systems, leads to unrestricted tumor cell growth. A clinical example of this principle is suggested by Hodgkin's disease, which is characterized by profound defects in cell-mediated immunity. Macrophages from patients with Hodgkin's disease produce PGE at four times the normal ratC 8. In vitro, the addition ofindometacin or the removal of glass adherent cells from lymphocyte cultures almost totally reverses the depressed P H A responses of cells from Hodgkin's disease patients. Patients with head and neck cancers often have high concentrations of PG-sensitive suppressor cells, and treatment with indometacin may induce tumor regression 19, although this is not a common finding. Some tumors secrete PG both in vivo and in vitro ~8. In these clinical cases, the concentration of specific arachadonic acid metabolites in the urine or plasma often serves as a marker for the rate of tumor growth and the clinical outcome of the diseasC 8. Some PGs induce hypercalcemia 17. PGE-mediated hypercalcemia often occurs in patients with carcinoma of the lung, breast, pancreas, kidney, or parotid gland. The source of PGE appears to be the tumor itself. PGE production and concomitant hypercalcemia may be reversed by the administration of aspirin or indometacin 17. Certain cancers, notably breast carcinoma and squamous cell cancers of the head and neck, are associated with intense inflammation, and PG involvement is suspected, some of which is produced by 'suppressor monocytes' associated with the disease 2°. Kaposi's sarcoma, a tumor of vascular origin, produces PG which may mediate the disseminated intravascular coagulation and hemorrhage associated with the disease and contribute to an immunologic deficit in these patients. Chronic infections and inflammatory disease The macrophage is thought to play a key role in the pathogenesis of rheumatoid arthritis. Cells isolated from patients secrete large amounts of PGE 2 and PGF2~ in vitro and the rate of PG synthesis correlates with the activity of the disease zl. Exogenous PGE1 administered in pharmacologic doses suppresses adjuvant arthritis in rats 1 and has greatly prolonged survival of SLE diseased N Z B / W and MRL/1 mice. In MRL/1 mice, the administration of PGE I also prevents the tremendous hyperplasia of the T lymphocyte compartment which characterizes the naturally occurring disease. A role has also been suggested for P G synthesis in the immune depression associated with disseminated coccidioidomycosis, sarcoidosis, and bovine brucellosis la. Traumatic injuries The release of large amounts of PG (including PGE2) has been particularly well documented as a direct consequence of human burn injuries 22. While the role of PG in the vascular changes and dermal ischemia which follow injury is well established, the participation of PG in the

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immunologic changes observed following injury have been addressed only recently. We have found that the concentration of PGE in the sera of patients with major burns is generally high (1 000-3 000 pg m1-1 compared with less than 100 pg rnl- ~in normal subjects) and that these sera often significantly suppress in-vitro lymphocyte responsiveness 23. This suppression can,often be reduced by delipidation of the sera, or by the addition of monospecific anti-PGE 2 (Ref. 23). Albumin binds PGE and may also have a role in PGs suppressive activity. Burn patients generally have a profound deficit of albumin. When suppressive burn sera are fractionated by gel filtration, the active material co-elutes with low molecular weight peptides, some of which we have identified as albumin fragments. We are currently investigating the possible participation of these fragments in the stabilization of PG in the sera and their possible contribution to suppressive activity. The literature is replete which descriptions of low molecular weight suppressive peptides associated with burn injury, surgical trauma, cancer, and other medical problems. It is possible that many of these suppressor substances owe their activity to associated PGs. [:]1 Acknowledgement Special thanks to Dr Alan Winkelstein, Professor of Medicine,

University of Pittsburgh School of Medicine, for his review of the manuscript and helpful suggestions. References 1 Zurier, R. B. (1982) in: Prostaglandins (Lee, J. B., ed.), pp. 91-112,

Elsevier, New York 2 Crunkhorn, P. and Willis, A. L. (1971) Br. J. Phaemacol. 41,507-512 3 Weissman, G.(1980) CurrentConcepts:ProstaglandinsinAcutelnflamrrultion, pp. 1-14, Upjohn Co., Kalamazoo 4 Penneys, N. S. (1980) Current Concepts: Prostaglandins and the Skin, pp. 11-17, Upjohn Co., Kalamazoo 5 Issekutz, A. C. and Movat, H. Z. (1982) Am. J. Pathol. 107,300-309 6 Rivkin, I., Rosenblatt, J. and Becker, E. L. (1975)J. lmmunol. 115, 1126-1134 7 Till, G., Kownatzki, E., Seitz, M. and Gemsa, D. (1979) Clin. hnmunol. Immunopathol. 12, 111-118 8 Peredes, J. M. and Weiss, S. J. (1982)J. Biol. Chem. 257, 2738-2740 9 Bankhurst, A. D., Hastain, E., Goodwin, J. S. and Peake, G. T. (1981) J. Lab. Clin. Med. 97, 179-186 10 Snider, M. E., FerteI, R. H. and Zwilling, B. S. (1982) Cell. Immunol. 74, 234-242 11 Gemsa, D., Seitz, M., Kramer, W., Till, G. and Resch, K. (1978)J. Immunol. 120, I187-1194 12 Cahill, J. and Hopper, K. E. (1982) Cell. Immunol. 67,229-240 13 Pelus, L. M. (1982)J. Ch'n. Invest. 70, 568-578 14 Ferraris, V. A. and DeRubertis, F. R. (1974)J. Clin. Invest. 54,378 386 15 Dy, M., Astoin, M., Rigaud, M. and Hamburger, J. (1980) Eur. ,]. ImmunoL 10, 121 126 16 Anderson, C. B., Jaffee, B. M. and C-raft, R. J. (1977) Transplantation 23, 444 447 17 Ziegler, J. L. (1982) Current Concepts: Cancer and the Prostaglandins, pp. 15-22, Upjohn Co., Kalamazoo 18 Goodwin, J. S. andWebb, D. R. (1980) Clin. lmmunol. Immunopathol. 15, 106-122 19 Kaneene, J. M. B., Anderson, R. K., Johnson, D. W. and Muscoplat, C. C. (1978) Infect. Immun. 22, 486-491 20 Balch, C. M., Dougherty, P. A. and Tilden, A. B. (1982)Ann. Su N, 196, 645-650 21 Blotman, F., Poubelle, P., Chalntreuil, J., Damon, M., Flandre, O., DePaulet, A. C. and Simon, L. (1982) Int. J. Immunophaemacol. 4, 119-125 22 Arturson, M. G. (1983)in: Traumatic Injury: Infection and Other Immunologic Sequelae (Ninnemann, J. L., ed.), pp. 57-78, University Park Press, Baltimore 23 Ninnemann, J. L. and Stoekland, A. E. (1984)J. Trauma 24, 201-207

Prostaglandin regulation of B-lymphocyte function Nigel D. Staite* and Gabriel S. Panayit The local production of prostaglandins (PGs) in tissues by monocytes, polymorphonuclear leucocytes, endothelial cells and platelets, and their rapid degradation, gives PGs an ideal opportunity for the selective regulation of inflammatory and immune responses. Much is known about the PG regulation of monocyte and T-cellfunction 1-~but our knowledge of PGmediated regulation of B-lymphocyte function is still very poor, with many apparent contradictions in the literature. Here Nigel Staite and Gabriel Panayi discuss the indirect and direct effects OfPGs on B-lymphocyte function with particular emphasis on the regulation of human lymphoeytes, acknowledging that most of what is known was learned from animal studies. PGs and antigen-speciflc antibody responses is increased by in-vivo administration of 1 pg of PGE2, The i.v. injection of sheep erythrocytes (SRBC) in mice PGFI, or PGF2~ (Ref. 6). Experiments in vitro show that results-2 min later in an increase in PGF2~ levels in the treatment of cell cultures with cyclo-oxygenase inhibitors spleen from 30 to 600 pg/mg -~ protein ~. Intravenous increases the secondary anti-SRBC response of primed soluble antigen, such as bovine ),-globulin (BGG) also murine spleen cells 7 and support the hypothesis that PGs stimulates PG production but more slowly, peaking after suppress immunoglobulin production in the mouse. 2 h. Antigen-induced PG production can be inhibited In rats, the spleen contains a phagocytic, adherent, with drugs such as indometacin given 24 h before injecsuppressor cell with macrophage-like characteristics. tion of SRBC. Furthermore, indometacin given before Their removal increases the secondary PFC response of SRBC increases the primary murine anti-SRBC spleen cells to heterologous erythrocytes a'9. 'Their supresponse in vivo 4'5, which suggests that PGs suppress antipressive effect seems to be mediated via PG since indobody responses in vivo. There is, however , conflicting metacin, aspirin and RO3-1314 (a compound with a evidence that the secondary plaque-forming cell response selective inhibitory action on cyclo-oxygenase) all in(PFC) of 5-6 week old dd/Y mice immunized with SRBC crease PFC responses in cultures of unseparated spleen cells - an effect abrogated by exogenous PGE 2 (Ref. 9). *Department of Medicine, Rheumatology Section, 14-169 Pretreatment of rats with 500/ag of PGEI subcutaneously Human Sciences, University of Minnesota, Minneapolis, twice a day for 14 days also suppresses primary antiMN55455, USA. SRBC responses in-vivo 1°. Thus, in both the rat and mouse antibody responses to SRBC measured by PFC *Depts of Medicine, Guy's Hospital Medical School, Guy's Hospital, London SE1 9RT, UK. are inhibited by PGs. © 1984,ElsevierSciencePublishersB.V., Amsterdam 0167 4919/84/$02.(Yd