A Th-2 chemokine, TARC, produced by keratinocytes may recruit CLA(+)CCR4(+) lymphocytes into lesional atopic dermatitis skin

Atopic dermatitis is an inflammatory skin disease in which the inflammation is characterized by the influx of lymphocytes into the dermis. It is gener ally believed that atopic dermatitis is a Th-2-type disease, i.e., the T ly mphocytes produce interleukin-1, interleukin-5, interleukin-10, and interle ukin-13, although it has become evident in recent years that the cytokine p rofile in the skin changes during the course of the disease towards a Th-1- Th-2 mixed cytokine profile (interferon-gamma, tumor necrosis factor alpha, and interleukin-2). The lymphocytes that home into the skin express cutane ous lymphocyte-associated antigen, and it has recently been shown that most of the lymphocytes in this population express the chemokine receptor CCR4. CCR4 is the receptor for the CC chemokine TARC (thymus and activation regu lated chemokine), and this chemokine is expressed predominantly by keratino cytes in the basal layer of the epidermis of lesional atopic dermatitis ski n in mice. In humans, however, it was shown to be expressed in the endothel ial cells of the dermis, We have examined the peripheral blood mononuclear cells of atopic dermatitis patients for the expression of cutaneous lymphoc yte-associated antigen and CCR4 and compared them with peripheral blood mon onuclear cells from normal controls. We found that the proportion of CLA(+) CCR4(+) lymphocytes is upregulated in atopic dermatitis patients. In additi on we have examined skin biopsies of lesional and non-lesional skin from at opic dermatitis patients and found that the keratinocytes, but not the endo thelial cells, produce TARC in the lesional but not in the nonlesional skin . To gain insight in the stimulatory mechanisms for TARC production in kera tinocytes, as previously observed in mice, we cultured HaCaT cells and foun d that interferon-gamma and tumor necrosis factor alpha work synergisticall y to induce TARC production. These observations suggest that the induction of TARC production in keratinocytes plays an important role in the late pha se skin invasion by CCR4(+)CLA(+) Th-2-type lymphocytes in atopic dermatiti s.