Cytokines

Background

Cytokines are cell intercellular messengers responsible for signalling an incredible variety of cell functions. The roles and functions of cytokines are confusing and still being sorted out. Over three dozen have been identified with more being discovered each day. Cytokines may have multiple functions and actions and different cytokines may have similar biological functions.

Broadly speaking, cytokines may be divided into several different classes. Even this organization is changing.

CLASS CHARACTERIZATION

Interferons (IFN) IFN-alpha, beta, and gamma

Interleukins (IL) IL-2, 4,5,9,10,12,13,14,15,17

Chemokines Platelet factor 4
IL-8
Macrophage inflammatory protein (MIP) 1 alpha
MIP1beta
RANTES (regulated on activation, normal T-expressed and secreted)
Monocyte chemotactic proteins 1,2,3, and 4

Inflammatory Cytokines Tumor necrosis factor (TNF)-alpha, beta
IL-1alpha
IL-1beta

Hematopoietic Growth Factors Granulocyte colony stimulating factor (G-CSF)
Granulocyte-monocyte (GM-CSF)
Monocyte (M-CSF)
Stem cell factor
Thrombopoietin
Erythropoietin

INDIVIDUAL CYTOKINES SITE OF PRODUCTION ACTIONS

IL-6 Macrophages, fibroblasts, endothelial cells, activated T-helper cells Marker of active disease in patients with interstitial cystitis

INTERACTIONS CHARACTERIZATION

ROLE WITH NF-kB

Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2.

Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, Wagner J, Edwards G, Clifford T, Menon S, Bazan JF, Kastelein RA.

DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304, USA

J Immunol 2001 Aug 1;167(3):1440-6 Abstract quote

IL-1 is of utmost importance in the host response to immunological challenges.

We identified and functionally characterized two novel IL-1 ligands termed IL-1delta and IL-1epsilon. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1delta and epsilon. Levels of keratinocyte IL-1delta are approximately 10-fold higher than those of IL-1epsilon. In vitro stimulation of keratinocytes with IL-1beta/TNF-alpha significantly up-regulates the expression of IL-1epsilon mRNA, and to a lesser extent of IL-1delta mRNA.

In NF-kappaB-luciferase reporter assays, we demonstrated that IL-1delta and epsilon proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1alpha and beta or IL-18. However, IL-1epsilon activates NF-kappaB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1delta, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1epsilon response.

In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1delta and epsilon and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1alphabeta/receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.

SKIN

Analysis of cytokine expression in dermatology.

Asadullah K, Sterry W, Volk HD.

Corporate Research Business Area Dermatology, Schering AG, Mullerstrasse 178, D-13342 Berlin, Germany.
Arch Dermatol 2002 Sep;138(9):1189-96 Abstract quote
During the past decade, the detection of cytokines has been a focus of scientific interest, including in dermatology. Dysregulation of cytokine production seems to be involved in the pathogenesis of various diseases. The determination of cytokine levels is of increasing diagnostic importance, and cytokines are used as therapeutic agents too. Cytokines are polypeptides secreted by a wide variety of cells in response to diverse stimuli, and mediate autocrine, paracrine, or endocrine effects that are often pleiotropic and redundant. Their molecular weight lies between 6 and 70 kd. The cytokines of immunologic relevance are primarily those that are formed by immune cells (monokines and lymphokines) and/or influence their function.

In principle, cytokines are detectable on 3 levels: (1) By using polymerase chain reaction, the messenger RNA expression of cytokine genes can be detected and, with the newer techniques, even quantified. (2) Protein synthesis can be detected by using bioassays and enzyme immunoassays or immunocytologic or immunohistologic detection of intracellular cytokine production. (3) Finally, there are indirect methods for the detection of cytokine formation by analysis of products of cytokine activity.

The immunobiological features of cytokines and the different approaches for cytokine determination are briefly discussed herein because basic knowledge of these biologically highly active messenger substances and the capabilities and limits of the individual detection methods are essential for a sensible interpretation of the relevant findings.

Clinical Lab News 2000;26:6-7.

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Last Updated 10/2/2002

CLASS	CHARACTERIZATION
Interferons (IFN)	IFN-alpha, beta, and gamma
Interleukins (IL)	IL-2, 4,5,9,10,12,13,14,15,17
Chemokines	Platelet factor 4 IL-8 Macrophage inflammatory protein (MIP) 1 alpha MIP1beta RANTES (regulated on activation, normal T-expressed and secreted) Monocyte chemotactic proteins 1,2,3, and 4
Inflammatory Cytokines	Tumor necrosis factor (TNF)-alpha, beta IL-1alpha IL-1beta
Hematopoietic Growth Factors	Granulocyte colony stimulating factor (G-CSF) Granulocyte-monocyte (GM-CSF) Monocyte (M-CSF) Stem cell factor Thrombopoietin Erythropoietin

INDIVIDUAL CYTOKINES	SITE OF PRODUCTION	ACTIONS
IL-6	Macrophages, fibroblasts, endothelial cells, activated T-helper cells	Marker of active disease in patients with interstitial cystitis

INTERACTIONS	CHARACTERIZATION
ROLE WITH NF-kB
Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, Wagner J, Edwards G, Clifford T, Menon S, Bazan JF, Kastelein RA. DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304, USA	J Immunol 2001 Aug 1;167(3):1440-6 Abstract quote IL-1 is of utmost importance in the host response to immunological challenges. We identified and functionally characterized two novel IL-1 ligands termed IL-1delta and IL-1epsilon. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1delta and epsilon. Levels of keratinocyte IL-1delta are approximately 10-fold higher than those of IL-1epsilon. In vitro stimulation of keratinocytes with IL-1beta/TNF-alpha significantly up-regulates the expression of IL-1epsilon mRNA, and to a lesser extent of IL-1delta mRNA. In NF-kappaB-luciferase reporter assays, we demonstrated that IL-1delta and epsilon proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1alpha and beta or IL-18. However, IL-1epsilon activates NF-kappaB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1delta, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1epsilon response. In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1delta and epsilon and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1alphabeta/receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.
SKIN
Analysis of cytokine expression in dermatology. Asadullah K, Sterry W, Volk HD. Corporate Research Business Area Dermatology, Schering AG, Mullerstrasse 178, D-13342 Berlin, Germany.	Arch Dermatol 2002 Sep;138(9):1189-96 Abstract quote During the past decade, the detection of cytokines has been a focus of scientific interest, including in dermatology. Dysregulation of cytokine production seems to be involved in the pathogenesis of various diseases. The determination of cytokine levels is of increasing diagnostic importance, and cytokines are used as therapeutic agents too. Cytokines are polypeptides secreted by a wide variety of cells in response to diverse stimuli, and mediate autocrine, paracrine, or endocrine effects that are often pleiotropic and redundant. Their molecular weight lies between 6 and 70 kd. The cytokines of immunologic relevance are primarily those that are formed by immune cells (monokines and lymphokines) and/or influence their function. In principle, cytokines are detectable on 3 levels: (1) By using polymerase chain reaction, the messenger RNA expression of cytokine genes can be detected and, with the newer techniques, even quantified. (2) Protein synthesis can be detected by using bioassays and enzyme immunoassays or immunocytologic or immunohistologic detection of intracellular cytokine production. (3) Finally, there are indirect methods for the detection of cytokine formation by analysis of products of cytokine activity. The immunobiological features of cytokines and the different approaches for cytokine determination are briefly discussed herein because basic knowledge of these biologically highly active messenger substances and the capabilities and limits of the individual detection methods are essential for a sensible interpretation of the relevant findings.