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Fig. 4. The role of cytokines in controlling cellular interactions involved in the immune and inflammatory responses. In an immune response, cells present antigens and release IL-1 to activate appropriate T-helper cells and IL-6, which acts as a B-cell differentiation factor. Activated T-helper cells produce a variety of cytokines, including lymphocyte growth (IL-2 and IL-4) and differentiation (IFNy and IL-10) factors and hemopoietic growth factors (IL-3 and GM-CSF). Macrophages can also be activated by antigen nonspecific mitogens such as LPS. Cytokines released include those with proinflammatory activities such as IL-1 (5, TNFa, and IL-8, as well as the anti-inflammatory IL-6.

different cells, including activated T cells, resting and activated B cells, macrophages, and mast cells (B20, B41, C2, E9, LI 7, R16, R17, W8, Z7). Interestingly, IL-2 and IL-4 act as autocrine growth factors, in that T cells secreting IL-2 express IL-2 receptors and proliferate in response to IL-2 but not to IL-4. The situation is reversed for IL-4. Indeed, IL-4 will inhibit the response of T cells to IL-2 (M9). Both IL-2 and IL-4 also stimulate the proliferation of Tc cells although apparently by distinct mechanisms. It would seem then that these two cytokines have complementary but subtly different roles, activating and stimulating proliferation in distinct populations of T cells, as a result of which the nature of an immune response to a particular antigen is subtly adjusted (L21, M52). There is evidence that preferential stimulation of particular T-cell subsets can contribute to the pathology of a disease. Different mouse strains infected with Leishmania exhibit different forms of disease. One strain with high IL-4 and IgE but low IFNy shows poor delayed-type hypersensitivity responses, suggesting overactive TH2 cells, and develops a severe generalized form of disease. Another strain with low IL-4 and IgE has a milder localized infection. Injection of antigen-specific TH1 clones into infected mice clears infection, whereas injection of TH2 cells exacerbates infection (L21, M52).

3.2.2. B-Cell Physiology

Cytokines from both types of activated T cells, as well as those from antigen presenting cells, act in concert to regulate B-lymphocyte proliferation and differentiation (C3, 02). As described earlier TH2 cells produce IL-4 and IL-5, which together influence the switch toward IgE and IgA (R20, Y4). On the other hand the Th1 cytokines IFNy and IL-2 also influence immunoglobulin production. IFNy antagonizes the action of IL-4, so that IL-2 and IFNy acting together can induce production of IgG (K16). The macrophage-derived cytokine IL-6 also acts on activated B cells, stimulating the general synthesis of immunoglobulin (R6). It therefore seems likely that the nature of an antibody response is determined by the cytokine profile associated with a particular immune response; THl cells will tend to stimulate IgM and IgG antibodies, whereas TH2 cells will stimulate IgA and IgE antibody synthesis.

3.2.3. Myelopoiesis

Many cytokines play a role in myelopoiesis (Fig. 5). An important group includes the CSFs that stimulate proliferation of developing macrophage and granulocyte populations (M23). In addition to their proliferative role, these cytokines may be involved in triggering differentiation, maintaining cell viability, and functional stimulation of mature macrophage and granulocytic cells. The action of these cytokines has been interpreted in terms of the differentiation stage of the responsive cells, so that pluripotent stem cells respond to IL-3, giving rise to a wide range of cell types, whereas M-CSF and G-CSF act on relatively late-stage cells, which have only the potential to develop into a macrophage or a granulocyte (M30, S50). While it is clear that each CSF can act on its own specific receptor (M56, P3), there are reports describing the cross-reactivity of colony stimulating factors on each other's receptors (P2). It is also clear that different CSF receptors can be expressed at the same time on the same cell (C8, P4) and that they regulate expression of each other's receptors (K27, P3). Evidence suggesting receptor heterogeneity for some CSF receptors is also beginning to accumulate (C8, P2). It is thus likely that different CSFs act in a complex but coordinated fashion to control differentiation and proliferation of myeloid cells.

Several cytokines other than the CSFs also play a role in myelopoiesis; for instance, IL-6 has been shown to hasten the emergence of blast cell colony forming cells in the presence of IL-3 (L8). It has also been demonstrated that all of the CSFs can induce production of IL-6 in normal myeloid cells and that IL-6 can induce production of GM-CSF and expression of receptors for GM-CSF, IL-3, and G-CSF in leukemic cells (SI). Cytokines that do not have a direct effect on myeloid cells can still effect myelopoiesis indirectly by inducing synthesis of other cytokines. IL-1 has been shown to induce production of IL-6 and CSFs from a variety of cell types, including macrophages, lymphocytes, stromal cells, and endothelial cells present in the bone marrow (S28). A stromal cell factor that supports the long-term culture of B cells has been characterized and called IL-7 (H39). This cytokine plays an important role in maintaining a population of pre-B lymphocytes, although it does not appear to stimulate differentiation of pre-B cells to B cells. In summary, combinations of cytokines acting in both an autocrine and a paracrine fashion may be required for properly regulated proliferation and differentiation of myelopoietic cells (D10, K14, P18).

3.2.4. Pathological Aspects

In malignant disease, the major interest lies in the suggestion that IL-6 may be a growth factor for plasma cells in myeloma. At the moment the evidence is interesting, but the conclusions are controversial.

In 1972 Namba and Hanaoka (N5) showed that pristane-induced plasmacytomas in BALB/C mice depended for their in vitro growth on a monocyte-derived factor, at that time unidentified, but subsequently shown to be IL-6. A murine plasmacytoma cell line with a gene insertion upstream of the IL-6 gene was found to constitutively produce IL-6. Further studies showed that in culture mouse plasmacytomas could be rendered dependent on IL-6 for growth, which could be blocked by antibodies to IL-6 or its receptor. If such cells were transfected with IL-6 cDNA, they showed autonomous growth and tumorigenicity when they were transplanted in mice. Growth of subsequent tumors in vivo could be inhibited and" even reversed by monoclonal antibodies capable of blocking the binding of IL-6 to its receptor. Further evidence was provided by the finding that massive lethal plasmacytomas occurred spontaneously in transgenic mice bearing a human IL-6

  1. 5. The role of cytokines in controlling hemopoiesis. Many cytokines play a role in hemopoiesis by stimulating the proliferation and differentiation of cells derived from a pluripotent stem cell population. Early differentiation events take place in the bone marrow, where IL-3, GM-CSF, and IL-7 appear to have important stimulatory roles. TGF(3 is a negative regulator of early cell differentiation. B-lymphocyte and myeloid cell development continues in the bone marrow while T-lymphocyte development is completed in the thymus. A large number of cytokines have been suggested to act on immature cells to encourage linage specific development.
  2. 5. The role of cytokines in controlling hemopoiesis. Many cytokines play a role in hemopoiesis by stimulating the proliferation and differentiation of cells derived from a pluripotent stem cell population. Early differentiation events take place in the bone marrow, where IL-3, GM-CSF, and IL-7 appear to have important stimulatory roles. TGF(3 is a negative regulator of early cell differentiation. B-lymphocyte and myeloid cell development continues in the bone marrow while T-lymphocyte development is completed in the thymus. A large number of cytokines have been suggested to act on immature cells to encourage linage specific development.

gene fused with the immunoglobulin heavy-chain enhancer, giving rise to high levels of constitutive IL-6 production. However, such plasma cells did not produce transplantable tumors, nor did they contain apparent c-myc gene rearrangements, which are observed in almost all pristane-induced plasmacytoma cells that form transplantable tumors. Such evidence strongly suggested a possible role for IL-6 in plasmacytomas, although clearly other factors or events were required for full tumorigenesis.

Freeman et al. (F26) demonstrated that in four cases of myeloma that they studied, IL-6 mRNA was expressed in the myeloma cells. In addition cytoplasmic IL-6 was detectable. These findings have been difficult to repeat and other workers have suggested that bone marrow-adherent cells (monocytes) rather than plasma cells are the source of IL-6 in the bone marrow of myeloma patients. However, further studies have shown that the plasma cells from about 50% of myeloma patients are responsive to IL-6 in short-term culture and that antibodies specific for IL-6 inhibit spontaneous uptake of tritiated thymidine, thus suggesting that IL-6 may be acting as an autocrine growth factor. Furthermore, the growth inducing activity of IL-1 and TNF on freshly isolated myeloma cells is blocked by antibodies to IL-6. Cytokines other than IL-6 may also play a role in myeloma. IL-3 appears to act synergistically with IL-6 (B26), whereas IL-4 acts to inhibit the growth of freshly isolated myeloma cells (T6). Klein (Bll) from Montpelier was able to show that the in vitro IL-6 response of myeloma cells obtained from patients with multiple myeloma was directly correlated with the in vivo labeling index of these tumors and that serum IL-6 levels, which were frequently raised in these patients, correlated well with disease severity.

The experimental analogue of the transgenic mouse in humans is cardiac myxoma. Patients with this condition frequently show evidence of autoimmune disease, polyclonal hypergammaglobulinemia, fever, and increases in acute phase proteins. These changes are associated with very high serum levels of IL-6, which has been shown to be expressed by the myxoma cells themselves. Extensive marrow plasmacytosis occurs in this condition, which is reversed upon removal of the tumor. However, malignant transformation and myelomatosis have not been described (J5). A comparable but more complex condition is Castleman's disease, in which activated B cells in the germinal centers of hyperplastic lymph nodes produced IL-6. Symptoms similar to those of cardiac myxoma were seen and, in one case, malignant myeloma developed. The nature of Castleman's disease is, however, unclear, and viruses or other factors activating the lymph node B cells are likely.

There is thus tantalizing evidence to suggest that deregulation of gene expression for IL-6 could be instrumental in the polyclonal plasmacytoma process and the generation of blood cell neoplasias. In many malignant lymphomas, as with pristane-induced plasmacytomas in mice, there is translocation of c-myc to the chromosomal location of the immunoglobulin genes, which are normally highly transcribed, and the c-myc protein is thus constitutively produced at high levels. In normal B lymphocytes c-myc is only transiently expressed early in the cell cycle and in response to growth promoting cytokines. The c-myc gene product is a DNA binding nuclear transcription factor. In developing follicular B cells IL-6 appears to induce expression of the BclW oncogene product that is associated with the mitochondria. The questions that arise are thus of great interest. Is this mutation necessary for IL-6 response? As with many tumors, is the progress from plasmacytoma to malignant transformation a multistep process? Why are the data from different groups apparently in contradiction? Does the newly described IL-6 inhibitor have a role to play? It is produced along with IL-6 by granuloma-derived macrophages. Could it be that, under some circumstances of culture, it is produced by myeloma cells to inhibit responsiveness to exogenous IL-6 and could it play a role in therapy?

In man a surprising number of myelopoietic growth factors have been mapped to a region on the long arm of chromosome 5, frequently associated with translocation events or deletions seen in leukemia (R29). Genes coding for GM-CSF, M-CSF, IL-3, IL-4, IL-5, and the cellular receptor for M-CSF have been located in the 5p23-35 region. Evidence from both in vitro and in vivo systems suggests that these cytokines, which play a central role in the up-regulation of myelopoiesis and in increasing the rate of release of blood cells into the circulation, may contribute to leukemia if they are inappropriately expressed as a consequence of gene translocation or deletion (R29).

3.3. Cytokines and Sepsis

Cytokines are peptide molecules that are produced by or act on cells of the immune and inflammatory systems. These molecules regulate the local and systemic events of the immune response, inflammation, hematopoiesis, and wound healing (B22, B65, H17, L10, W25). It is not surprising then to find cytokines playing an important role in those processes, following trauma, that lead to multiple organ failure (MOF) (Fig. 6). At the simplest level there are two major factors that contribute independently to MOF, shock, and septicemia. The role of cytokines in septicemia has been extensively examined and is considered later. The role of cytokines in shock is less well understood and is not considered any further here, except to note a recent report suggesting the presence of high levels of TNF when hemorrhage accompanies trauma but not following trauma alone (A18, A19).

3.3.1. Trauma-Induced Immune Suppression

In spite of aggressive antibiotic therapy and the practice of good hygiene, systemic bacterial infection is frequently a serious complication following trauma and one that can result in MOF (Fl). Perhaps the most important factor contribut-

  1. 6. The role of cytokines in the antigen-independent activation of monocytes and T lymphocytes. Gram-negative endotoxins. Cells of the monocyte/macrophage linage can be activated by bacterial endotoxins such as LPS to produce proinflammatory cytokines, especially IL-ip, TNFa, and IL-8. IL-ip produced by activated macrophages will stimulate T-helper cells to produce I FN-/ and TNFfi. Gram-positive enterotoxins. Many enterotoxins such as toxic shock syndrome toxin-1 can cross-link the T-cell receptor and macrophage MHC class II antigens activating both cells to produce the same spectrum of cytokines as endotoxin activated cells. The proinflammatory cytokines IL-1 and TNF stimulate production of inflammatory mediators such as reactive oxygen species, platelet activating factor, eicosanoids, and proteolytic enzymes. IL-8 is chemotactic for PMN. In concert with IFNv, TNF is cytostatic and cytotoxic for cells. IL-6 acts as an anti-inflammatory molecule stimulating the production of glucocorticoids and acute phase proteins.
  2. 6. The role of cytokines in the antigen-independent activation of monocytes and T lymphocytes. Gram-negative endotoxins. Cells of the monocyte/macrophage linage can be activated by bacterial endotoxins such as LPS to produce proinflammatory cytokines, especially IL-ip, TNFa, and IL-8. IL-ip produced by activated macrophages will stimulate T-helper cells to produce I FN-/ and TNFfi. Gram-positive enterotoxins. Many enterotoxins such as toxic shock syndrome toxin-1 can cross-link the T-cell receptor and macrophage MHC class II antigens activating both cells to produce the same spectrum of cytokines as endotoxin activated cells. The proinflammatory cytokines IL-1 and TNF stimulate production of inflammatory mediators such as reactive oxygen species, platelet activating factor, eicosanoids, and proteolytic enzymes. IL-8 is chemotactic for PMN. In concert with IFNv, TNF is cytostatic and cytotoxic for cells. IL-6 acts as an anti-inflammatory molecule stimulating the production of glucocorticoids and acute phase proteins.

ing to serious infection in traumatized individuals is the immunosuppression that occurs as a result of trauma (A3, Fl, H28). Defects in T-cell-mediated immunity are readily demonstrated in trauma victims and there is also some evidence that PMN and macrophage functions are also suppressed (F2, M24, M35, R18, S46). The effect of such events is to weaken defenses against invading microorganisms. In particular the loss of PMN and macrophage function will predispose an individual to bacterial infection, whereas the loss of appropriate T-cell function will lead to a general inability to respond to the majority of invading microorganisms.

The mechanism by which immune suppression is brought about is not well understood, although it has been suggested that important mediators of T-cell suppression include the steroid hormones such as Cortisol, soluble IL-2 receptor, trauma-derived peptides, and acute phase proteins (C35, El, H28, 06, R18, S30, T7, T13). It is also possible that the impaired PMN and macrophage functions observed in trauma patients are not entirely the result of suppression but may be the result of excessive activation and depletion of functional cells from the circulation.

IL-6 has been suggested to play a major role in down-regulating inflammation, one consequence of which is immunosuppression. Important immunosuppressive actions of IL-6 are the induction of corticosteroids and acute phase protein synthesis. Corticosteroids are synthesized by the adrenal cortex largely under the control of pituitary ACTH. However, there is growing evidence that cytokines such as IL-6 can also regulate Cortisol production and that T cells make an ACTH-like molecule. IL-6 is able to act both at the hypothalamic level to induce corticotrophin releasing factor (CRF) and directly on the adrenal to induce Cortisol synthesis, and it has been suggested that IL-6 is particularly important in maintaining the long-term adrenal response to trauma (S5). Levels of IL-6 following trauma appear to correlate at least as well with Cortisol concentrations, which remain elevated after ACTH levels return to normal, as with CRP levels (PI). Corticosteroids such as Cortisol can potentially inhibit many aspects of the immune response; frequently these involve inhibition of cytokine synthesis (F13).

IL-6 appears to be the major mediator responsible for the control of acute phase protein synthesis (Hll, L7). Acute phase proteins contribute in many ways to the down-regulation of inflammation, inhibition of proteinases, mopping up of reactive molecules, and immunoregulation. One protein in particular has been suggested to be immunosuppressive, AGP (B25, C35). A possible mechanism by which AGP can mediate immunosuppression is by stimulating synthesis by macrophages of an inhibitor of IL-lra (see Section 2.7.1.) (B54).

A number of cytokines also play important roles in regulating other processes that might contribute to immunosuppression. SIL-2R is released by T lymphocytes stimulated to proliferate by IL-2. IL-1 and TNF induce the synthesis and release of proteinases that might contribute to the production of trauma-derived peptides. The effects of sIL-2R and trauma-derived peptides are probably particularly important at or close to the site of production; that is they are acting in a paracrine fashion.

3.3.2. Gram-Negative Septicemia

Gram-negative bacteria produce a cell wall component lipopolysaccharide (LPS) that, when purified and administered to animals, induces an acute phase response. If administered by an appropriate route and in sufficient quantity LPS can cause MOF (B4, N9) (Fig. 6). Cells of the macrophage/monocyte linage have been identified as important cellular targets for LPS (A6, B7, L18, M26, M49). Isolated macrophages stimulated with LPS produce a variety of cytokines including IL-6, IL-ip, and TNFa. Two of these cytokines, IL-1 and TNF, are mediators of the local and systemic effects occurring during infection (B36, B39, D12, D21, K33, W12). The role of IL-6 was discussed earlier (see Section 3.3.1.). Administration of either IL-1 or TNF to animals has been shown to induce many of the effects observed in bacterial sepsis (T15). Elevated TNF levels have been reported in acute lethal sepsis. These observations have led to the suggestion that TNF may mediate MOF

(H2,14, K28, L25, M49). However, there is growing evidence that suggests that the role of TNF in MOF is not straightforward. In particular the reported levels of TNF and efficacy of antibodies against TNF are different in different models of lethal sepsis (B4). Systemic Escherichia coli infection induces high levels of circulating TNF, and antibodies to TNF inhibit the lethal consequences of infection. On the other hand, in compartmentalized infection, rat cecal ligation-induced peritonitis, no circulating or peritoneal TNF was detected and antibodies to TNF failed to inhibit lethal outcome. In another model, which used fecal material to infect the peritoneal cavity, circulating TNF levels were elevated but again antibodies failed to protect against lethal outcome (B4). Circulating TNF and IL-1 have been reliably detected only in the serum or plasma of individuals with severe acute sepsis. This may, however, be due to the presence of serum binding proteins masking lower levels of this cytokine (E6, G22, L3). Chronic administration of low doses of TNF does not mediate the effects of sepsis and when carefully investigated in animal models the effects of LPS and TNF are sometimes found to be different (K28, M55, R7). A more cautious view would be that TNF plays a major role only in some forms of sepsis and MOF. Interestingly it has been reported that the metabolic effects of TNF are different, depending on the site of production (T18). Another example of MOF resembling compartmentalized sepsis but in which bacterial infection is not apparent is severe acute pancreatitis. Recent investigations suggest that excessive PMN activation is a characteristic of this disease but that circulating levels of TNFa are not significantly different from those of TNFa with mild disease (B8). The implication being either than macrophages are not activated to produce TNFa or that any TNF produced is utilized locally.

3.3.3. Gram-Positive Septicemia

Gram-positive bacteria can also give rise to septicemia and multiple organ failure. Whereas this path to MOF may be less dramatic and more easily controlled, the cellular basis of gram-positive septicemia provides an interesting adjunct to that of gram-negative sepsis. Gram-positive bacteria produce toxins, so-called "super antigens," which act by cross-linking MHC antigens on macrophages with the T-cell antigen receptor (L2, L12, R14, U2) (Fig. 6). This cross-linking stimulates the T cells to produce mediators such as IL-1, TNF, and IFNy (F19, M32, Ul) that participate directly in mediating an inflammatory response and stimulate macrophages to produce IL-1 (5 and TNFa as well as other mediators that amplify the inflammatory stimulus (D6, G25). Subsequent events probably resemble those of gram-negative-induced MOF.

3.3.4. Cytokines in the Activation of Polymorphonuclear Leukocytes and Macrophages

Whereas the evidence that TNF acts as a systemic mediator of MOF is controversial, the role of this cytokine along with IL-1 in mediating local tissue damage is now attracting the attention of investigators. A number of different cytokines are potentially involved in the recruitment and activation of PMN and macrophages, including the proinflammatory cytokines, IL-1, TNF, and IL-8. Of particular interest are IL-1 and TNF, which can be produced by macrophages and other cells in, and close to, traumatized tissues or by LPS-stimulated macrophages at distant sites. These cytokines have multiple roles in cell activation. They induce expression of adhesion molecules on endothelial cells, facilitating recruitment of leukocytes from the circulation (C30, L5, L34, Z3). Many of the products produced by cells or the reticuloendothelial system in response to TNF can contribute to MOF: reactive oxygen species (D32, K3, W10), proteolytic enzymes, complement components (D4, H36, K5), eicosanoids (K29, L19, M44, M57), and platelet activating factor (M28, Rl, S54). TNF and IL-1 induce the synthesis of themselves and each other by a variety of different cells, effectively amplifying the inflammatory response (A9, C32, H25, L23, S53, W21).

There is considerable evidence that TNF can effect many leukocyte activities and might be regarded as a systemic effector molecule for MOF. However, as mentioned earlier, the correlation of circulating TNF levels and MOF in some animal models with severe acute pancreatitis is not convincing. It remains possible that another mediator produced by LPS-stimulated macrophages is responsible for the events leading to MOF (M25, T9). Whatever the role of TNF as a systemic mediator, TNF may act together with other cytokines such as IL-1 and IL-8 in closed compartments to regulate many of the tissue damaging effects contributing to MOF.

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