Inflammatory mediators

Tumor necrosis factor-a, IL-1b, and IL-6 are the archetypal proinflammatory cytokines, and they can all influence immune cell function, inhibit lymphocytes, and alter normal phagocyte function (Mannick...19.9.3). IL-6 has a role in the immune response to infection and is synergistic with platelet activating factor in neutrophil priming, possibly leading to an inappropriate inflammatory response. IL-10, the classic anti-inflammatory cytokine, suppresses T cells. IL-4 promotes T- and B-cell proliferation, macrophage expression of class II molecules, and antigen presentation, but inhibits macrophage expression of the LPS receptor CD14 and the release of nitric oxide and proinflammatory cytokines. IL-2, secreted by helper T cells, promotes lymphocyte survival and activation and is central to the appropriate function of the adaptive immune response. Critical illness is associated with impaired IL-2 production, and serum from critically ill patients inhibits IL-2 production by normal T lymphocytes. Not only is the serum immunosuppressive, but wound fluid similarly decreases lymphocyte proliferative responses in vitro.

The nature of the serum suppressive factor(s) remains to be elucidated, but IL-10, transforming growth factor-b, prostaglandin E 2, and nitric oxide all have some of these characteristics. Macrophages release hydrogen peroxide and prostaglandin E 2, both of which reduce B-cell responses. Prostaglandin E2 is a powerful inhibitor of lymphocyte activation and, together with prostacyclin (prostaglandin 12), can inhibit phagocyte activation and cytokine release ( MannickJ993). Nitric oxide, a constitutive product of the endothelium, is released in large amounts by activated macrophages and can promote or suppress immune function. Lymphocyte proliferation is inhibited by elevated levels of nitric oxide. However, this is complicated as low levels of nitric oxide production are probably necessary for optimal peripheral blood lymphocyte function and for microbial killing, with augmentation above a threshold progressively impairing immune responses by inhibiting the antigen-specific secondary immune response of primed lymph node cells. Likewise, although nitric oxide is important for normal macrophage antimicrobial action, high levels suppress phagocytosis, free-radical production, and protein synthesis and lead to macrophage apoptosis ( Albina and ReichneL^QS). Modifications of cytokines, colony-stimulating factors, and growth factors by acute phase reactants, heat shock proteins, and changes in cytokine receptor expression lead to a complex acute phase response (Pannen..and Robotham 1995).

Reactive oxygen intermediates (including superoxide, hydrogen peroxide, hydroxyl radical, and peroxynitrite) are essential for appropriate bactericidal activity. They are produced in abundance, and can lead to widespread damage of DNA, proteins, and membranes and cell death if not balanced by antioxidants including albumin, vitamin E, and the enzymes superoxide dismutase, catalase, glutathione synthase, and glutathione reductase. Heat shock proteins and acute phase response proteins also protect cells against endotoxin and reactive oxygen intermediate cell death. For example, serum amyloid-A protein binds to neutrophils, reducing their oxidative burst. These acute phase response products may also mediate immunosuppression; a B-cell-suppressive effect of serum amyloid-A protein has been described. Furthermore, receptor shedding and soluble receptors and adhesion molecules further modulate the balance between pro- and anti-inflammatory responses.

Many inflammatory mediators can directly influence the function of cells of the immune system. However, it is difficult to dissect the exact role of each mediator, as the response of cells cultured in vitro in the presence of a single inflammatory mediator will be very different from that of cells in vivo in the presence of the whole milieu of pro- and anti-inflammatory agents.

In general it is fair to surmise that the proinflammatory mediators are important natural components of an effective inflammatory response which includes appropriate immune function. Only when activated to excess do they exert detrimental effects, which can include effects on immune function. Likewise, the body naturally produces anti-inflammatory mediators that exert a balancing influence on the inflammatory response; however, overexpression of these factors may also impair immune responses. Both excessive immune cell activation from proinflammatory responses and, at different times, excessive immunosuppression from anti-inflammatory mediators probably contribute to the immune dysfunction seen in critical illness ( Bone 1996).

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