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.
- infection- or injury-related challenge: 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
- level and duration of response must be appropriate to the challenge

Cytokines
- soluble polypeptide mediators
- influence many aspects of leukocyte function, and in immune system and homeostatic control
- Therapeutic targeting of cytokines has proven valuable in treating dermatologic disorders.
Chemokines
- play roles in angiogenesis, neural development, cancer metastasis, hematopoiesis, and
infectious diseases.

TABEL 12-3

IL-1

- Several biologics that act by inhibiting IL-1 func- tion have been developed for clinical use

TUMOR NECROSIS FACTOR

- TNF- important mediator of cutaneous inflammation
- stimulation with LPS or UV light  strong induction of TNF  LC migration  sensitization
of naïve T cells.
- Therapeutic implications
1. anti– TNF-antibody (infliximab, adalimumab)
2. soluble TNF receptor (etanercept)
several autoimmune and inflammatory dis-eases
- TNF antagonists
1. powerful immunomodulating drugs
2. appropriate caution is required

IL-17
- defense against pathogenic species of extracellular bacteria and fungi
- block of development: recurrent skin infections with Staphylococcus aureus and Candida albicans.
- closely linked to autoimmune disease
- Therapeutic implications
1. human monoclonal anti-bodies against IL-17A
2. secukinumab and ixekizumab
3. moderate to severe chronic plaque psoriasis
FIGURE 12-7

Interleukin-4 and Interleukin-13:

- mediators of atopic immunity

- therapeutic targeting of IL-4: proven beneficial in the treatment of atopic dermatitis.

Interleukin-9 and Interleukin-21:

- with IL-4 and IL-13, function as effectors of allergic

- mediate antimelanoma activity.

INTERLEUKIN-6

- important cytokine for skin and is subject to dysregulation in several human diseases,
including some with skin manifestations.
- produced by keratinocytes, fibroblasts, and vascular endothelial and leukocytes infiltrating the
skin.
- Expression elevated in some diseases (psoriasis, kaposi sarcoma)
- stimulate the proliferation of human keratinocytes

INTERLEUKIN-11

- inhibits production of inflammatory cytokines

- therapeutic activity in patients with psoriasis.

IL-31

- important mediator of cutaneous allergic diseases and atopic dermatitis

- stimulate itch
- acts directly to inhibit keratinocyte differentiation and filaggrin expression
- impairs skin barrier function in atopic dermatitis.
- Therapeutic implications
1. efficacious in decreasing pruritus and sleeplessness.

INTERFERON -α and -β

o Modulates T-cell response  inhibits cell proliferation

o Treats some types of cancer
o clinically useful antiviral and tumor inhibitory effects

o (genital warts, superficial basal cell carcinoma, and actinic keratoses.)

Interleukin-10:

- An “Antiinflammatory” Cytokine
- major source: epidermal keratinocytes
- UV irradiatio  keratinocyte IL-10 production  immunosuppressive effects
- Dampens cutaneus immune and inflammatory responses
Therapeutic implications

Cytokine- based therapeutics

(+) offer a more targeted approach

(-) immunosuppressive, may increase the risk of infections and malignancy.

CHEMOKINES

- guide leukocytes via chemotactic gradients in tissue.

- increase the binding of leukocytes
- firm adhesion and extravasation of leukocytes in tissue.
o C
o CXC (α-chemokines)
o CC (β- chemokines).
o CXXXC (CX3C).
- Role of chemokines in recruitment of host defense cells
o provide the signal causing leukocytes to come to a complete stop (ie, arrest) in blood vessels at
inflamed sites
o transmigration of leukocytes from the luminal side of the blood vessel to the abluminal side
o attract leukocytes to sites of inflammation in the dermis or epidermis
- Keratinocytes and endothelial cells: rich source of chemokines when stimulated by appropriate
cytokines.
- play critical roles in the emigration of resident skin DCs to draining LN

CHEMOKINES IN DISEASE
ATOPIC DERMATITIS

- CCR4 and CCR10: Recruits T cells to atopic skin

- CCL18: attracts CLA+ memory T cells to the skin
- eotaxin and CCR3: recruitment of eosinophils and Th2 lymphocytes

PSORIASIS

- CCL17 and CCL20: T-cell migration to the epidermis

- CCR6: development of inflammation
- CXCR1 and CXCR: attracts neutrophils

MALIGNANCY

- Figure 12-12 Chemokine receptors in melanoma progression and metastasis. Chemokine receptors play
distinct roles in melanoma metastasis.117 CCR10 may enhance survival of primary melanoma tumors and
skin metastases. CCR7, CCR10, and, possibly CXCR4 may contribute to lymph node metastasis. CXCR4
appears to be involved in primary tumor develop- ment and metastasis at distant organ sites such as the
lungs. CCR9 has been implicated in melanoma small bowel metas- tasis in patients.
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