Cytokines are polypeptide mediators that function in communication between hematopoietic cells and other cell types.
Cytokines often have multiple biologic activities (pleiotropism) and overlapping biologic effects (redundancy).
Chemokines and their receptors are vital mediators of cellular trafficking.
Chemokines are synthesized constitutively in some cells and can be induced in many other cell types.
Cytokine and chemokine-based therapeutics now in use include recombinant cytokines, inhibitory monoclonal antibodies, fusion proteins composed of cytokine receptors and immunoglobulin chains, topical immunomodulators such as imiquimod, prevention of T-cell arrest on activated endothelium or blocking infection of T cells by human immunodeficiency virus 1 using CC chemokine receptor 5 analogs, and cytokine fusion toxins.
THE CONCEPT OF SOLUBLE MEDIATORS
When cells and tissues in complex organisms need to communicate over distances greater than one cell diameter, soluble factors must be used. A subset of these factors is most important when produced or released transiently under emergent conditions (Table 12-1). When faced with an infection- or injury-related challenge, the host must orchestrate a complex and carefully choreographed series of steps. It must mobilize certain circulating white blood cells precisely to the relevant injured area (but not elsewhere) and guide other leukocytes involved in host defense, particularly T and B cells, to specialized lymphatic tissue remote from the infectious lesion but sufficiently close to contain antigens from the relevant pathogen. After a limited period of time in this setting (ie, lymph node [LN]), antibodies produced by B cells and effector-memory T cells, can be released into the circulation and localize at the site of infection. Soluble factors produced by resident tissue cells at the site of injury, by leukocytes and platelets that are recruited to the site of injury, and by memory T cells ultimately recruited to the area, all coordinate an evolving and effective response to a challenge to host defense. Most important, the level of this response must be appropriate to the challenge, and the duration of the response must be transient, that is, long enough to decisively eliminate the pathogen but short enough to minimize damage to healthy host tissues. This chapter focuses on two major categories of soluble mediators that help regulate an effective immune response: cytokines and chemokines.
Table 12-1Primary Soluble Mediators Constitutively Expressed by Human Keratinocytes ||Download (.pdf) Table 12-1 Primary Soluble Mediators Constitutively Expressed by Human Keratinocytes
|MEDIATOR ||UPREGULATING STIMULI |
|IL-1α ||IL-1α, TNF-α, LPS, UVB, IFN-γ |
|IL-1α ||IL-1α, TNF-α, LPS, UVB |
|IL-1RA ||IL-1α, TNF-α, LPS, UVB, IFN-γ |
|IL-6 ||IL-1α, IFN-γ, IL-17, LPS |
|IL-18 ||TNF-α, UVB, LPS, dsRNA |
|TGF-α ||TNF-α, IFN-γ |
|TGF-β ||UVB, LPS, RA |
|CXCL8 ||TNF-α, IL-1α, IFN-γ, IL-17, UVB, dsRNA, flagellin |
|CCL17 ||IFN-γ, TNF-α |
|CCL20 ||TNF-α, IL-1α, IL-1β, IFN-γ, IL-17, CD40L, dsRNA |
|CCL27 ||TNF-α, IL-1β, dsRNA |