Regulatory pathways in inflammation.
Tuning is a key aspect of inflammatory reaction essential in homeostasis and pathology. An emerging mechanism for negative regulation of proinflammatory cytokines is based on non-signaling IL-1/TLR receptors and chemokine receptors competing with signaling receptors for ligand binding and sustaining ligand internalization and degradation. Biological activities of IL-1R/TLR receptors are under control of membrane-bound binding molecules lacking the signaling domain, soluble receptor antagonists, and intracellular signaling inhibitors. The chemokine system includes at least three 'silent' receptors with distinct specificity and tissue distribution. D6 is the best characterized representative member of this class of negative regulators, binds most inflammatory, but not homeostatic, CC chemokines and shuttles in a ligand-independent way from the plasma membrane to endocytic compartments where chemokines are targeted to degradation. In vitro and in vivo evidence, including results with gene targeted mice, is consistent with the view that these non-signaling receptors for proinflammatory cytokines possess unique functional and structural features which make them ideally adapted to act as a decoy and scavenger receptors, with a non redundant role in dampening tissue inflammation and tuning draining lymph nodes reactivity.
Mantovani
Alberto
A
Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Pathology, University of Milan, Italy. Electronic address: alberto.mantovani@humanitas.it.
Garlanda
Cecilia
C
Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
Locati
Massimo
M
Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Pathology, University of Milan, Italy.
Rodriguez
Tania Veliz
TV
Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
Feo
Safiye Gonzalvo
SG
Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
Savino
Benedetta
B
Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Pathology, University of Milan, Italy.
Vecchi
Annunciata
A
Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D054447:Receptors, CCR10 / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D000097628:Chemokine Receptor D6
D018925:Chemokines; D016207:Cytokines; D054447:Receptors, CCR10; D018121:Receptors, Cytokine; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D000097628:Chemokine Receptor D6