Il8

MCP1 Rantes

Complement proteins Most components classic and alternative pathway

Coagulation factors Several, including tissue factor

Adhesion, matrix molecules Fibronectin, thrombospondin, proteoglycan

Transport proteins Transferrin, B12-bindlng protein, apolipoprotein E. a2-Macroglobulin

Bioactive lipids

Cyclooxygenase and lipoxygenase products of arachidonate PAF

Reactive oxygen intermediates Superoxide anion, hydrogen peroxide, singlet oxygen, hydroxyl radicals Reactive nitrogen intermediates Nitric oxide, nitrites, nitrates

Defensins Polypeptides

Antimicrobial

Plasminogen activation and fibrinolysis, neutral proteinase activation

Connective tissue catabolism

Pressor

Lysosomal digestion

Multiple local and systemic host defense functions, e.g. endothelium, leukocytes, connective tissue Antiviral, immune modulation Acute phase response Inhibitor proinflammatory cytokines and APC functions Stimulates IFN-y production by NK and Th cells Fibroblast growth

Inhibitor activation of macrophages and other targets Granulocyte, macrophage and dendritic cell growth and differentiation Granulocyte chemoattractant Chemoattractant, hematopoietic regulator Monocyte recruitment Recruitment of monocytes and Th cells

Local osponization and complement activation

Local initiation and regulation of clotting

Localization, migration, modulation of cellular interactions and phagocytosis

Transport Fe, vitamin, lipid

Proteinase inhibitor

Mediators of inflammation, e.g. effects on leukocytes, small vessels

Platelet activation

Killing and stasis of microorganisms and cells by activated macrophages

Killing, microbial, parasitic, and cellular targets by IFN-y-activated macrophages

Antibacterial

Constitutive in vitro, inducible in vivo, myelomonocytic and Paneth cells

Inducible by macrophage activation, phagocytosis and cytokines

Inducible

Steroid inducible

Mainly intracellular

Endogenous pyrogens, tissue injury, weight loss. Superinducible

Also product TH2 cells

Chemokine family Chemokine family

Chemokine family

Other sources, e.g. liver

Other major sources Other major sources

Other sources

Macrophage has high-level arachidonate in membranes therefore potent source

Tissue injury, modulated by free radical scavengers iNOS inducible, compared with low levels of NOS constitutive in other tissues.

Note: NO not readily detectable in human monocyte/macrophage culture systems

Produced only by some macrophages as well as PMNs and Paneth cells

Some of these have not been demonstrated as products of immunologically activated versus other simulated Mo. Adapted from Gordon and Hughes (1997).

IL-10, is present. Secretory activities of activated Mb are tightly regulated by multiple external and intrinsic factors. Products of activated M0 such as IL-10 and TGFpJ, as well as IFNa/p, prostaglandins and antiproteinases, all serve to limit injurious M0 activities.

Intracellular pathogens utilize different strategies to subvert M0 activation

Microorganisms, including bacteria, viruses and parasites, utilize different uptake pathways and adopt a range of survival strategies to evade killing by activated M0 (Figure 4). The failure to trigger a respiratory burst may be connected to their survival; once within the M0, an organism may interfere with maturation of phagosomes, inhibit acidification and fusion with lysosomes, or lyse the vacuolar membranes. IFNy can reverse some of these processes, even when added after uptake of an organism. The vital role of IFNy and its receptor in resistance to various infections has been confirmed in mice and humans, including mycobacterial infection of subjects and experimental animals genetically lacking these molecules. It should be stressed that cytokines such as IL-10 that deactivate M0 and thus enhance susceptibility to infections and inflammatory injury, as in inflammatory bowel disease, are also able to inhibit entry or growth of other pathogens, such as HIV-1. It is therefore necessary to define the role of individual cytokines in M0 'activation' in relation to challenge by particular organisms.

Activation of M0 can mediate immunosuppression

If M0 are persistently activated by repeated antigenic stimulation, or fail to eradicate an intracellular pathogen, the cells themselves can become refractory to subsequent stimulation. One consequence may be a failure to produce a respiratory burst in response to a further surface stimulus. The mechanisms are poorly understood and include receptor downregul-ation as well as inhibition of intracellular signal transduction pathways. An in vitro example of failure to reactivate M0 to a repeated stimulus is seen after pretreatment with phorbol ester (PMA), which activates protein kinase C irreversibly. Activated Mb through cell-cell and secretory interactions with T lymphocytes and dendritic cells can also mediate immunosuppression. Examples include inhibition by alveolar Mb, via nitric oxide of antigen-induced proliferation of T lymphocytes. Other Mb products (reactive oxygen metabolites, TNFa, prostaglandins) have also been implicated in antigen nonspecific immunosuppression.

Phagocytosis

Mo responses

^T) Binding

^T) Binding

Engulfmertt

Phagosome lormalton

AckHlieaton

Proteolysis

Lysosomal fusion Digestion

Mombrarco d Eruption/ Ins ion

Figure 4 Stages of uptake of a hypothetical pathogen by macrophages. Receptors involved in phagocytic recognition are shown, as are potential steps of evasion of host killing mechanisms. Some of the Mu responses are listed. FA-11 (macrosialin, the murine homolog of CD68) is a pan-Me glycoprotein abundantly expressed in phagosomes. Selected phagocytic stimuli alter the glycoforms of this membrane molecule profoundly, possibly contributing to phagosomal membrane resistance to intravacuolar enzymes and acidification.

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