IL1 Receptors in the Skin

IL-1 receptor type 1 (IL-1R1) can bind both IL-1a and IL-1p resulting in the initialization of MyD88-dependent signaling (see below and Fig. 13.1). The receptor, expressed on the surface of a variety of cells, mediates all known biologic activities of IL-1 by initializing a cascade of events leading to the recruitment and activation of macrophages and neutrophils, vascular dilation, fever and a proinflammatory immune response. The central role of the IL-1 system is protection against microbial colonization and infection [53].

The second receptor for IL-1, IL-1R2, also binds both IL-1a and IL-1 p. By binding the functional ligands for IL-1R1, IL-1R2 serves to inhibit IL-1-mediated inflammatory responses [53].

IL-1 receptor antagonist (IL-1RA), the naturally occurring competitive inhibitor of IL-1 bioactivity, can bind only to IL-1R1 and not IL1R2. However, it does not induce signaling but reduces the IL-1-mediated inflammatory response. The IL-1RA gene is polymorphic, resulting in quantitative differences in both IL-1RA and IL-1p production. A tandem repeat sequence of 86 base pairs exists in the second intron of the IL-1RA gene. In different individuals, the number of times this sequence is repeated varies from two to six (Table 13.2). The frequency of the individual alleles varies among different ethnic or geographic populations, with the most frequent combinations being IL1RN*1 homozygotes or IL1RN*1/IL1RN*2 heterozygotes [73]. In patients with chronic inflam

Table 13.2. Gene polymorphisms in the second intron of the IL-1 receptor antagonist (IL1RN)

Gene

Allele

No. of repeatsa

Characteristics

IL1RN*1

1

4

Most common allele

IL1RN*2

2

2

Associated with prolonged inflammation

IL1RN*3

3

3

Rare

IL1RN*4

4

S

Rare

IL1RN*S

S

6

Rare

a Copies of the 86-base repeats a Copies of the 86-base repeats mation, such as inflammatory bowel diseases, alopecia areata, psoriasis, lichen sclerosus or lupus erythematosus, IL1RN*2 homozygosity increases the severity of the inflammation, suggesting that persons with this allele have a more prolonged and more severe proinflammatory immune response than do persons with other IL-1RA genotypes [73]. Interestingly, the frequency of the two-repeat allele of IL-1RN is increased among patients with acne conglobata but not among those with HS. In addition, IL1RN*2 homozygosity was detected only amongst patients with severe acne conglobata, suggesting that allele 2 of the IL-1RN gene may contribute to the development of acne conglo-bata but not HS [38].

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